The connection between Dr. Harold Griffith and Richard Gill: new insights into the history of curare use in anesthesia from previously unknown correspondence.

Dr. Harold R. Griffith and Richard C. Gill figure prominently in curare's storied history. In 1938, Gill returned from an Amazon expedition with over 11 kg of curare. After scientists at E. R. Squibb & Sons identified a plant source (Chondrodendron tomentosum) and isolated a stable extract of uniform potency (marketed as Intocostrin), Griffith administered it in the operating room in 1942, showing its advantages and safety. In this article, we report correspondence between Griffith and Gill, heretofore not appreciated, after finding a letter from Gill to Griffith affixed to the inside back cover of a book contained in a private library.Following the serendipitous discovery of this previously unknown letter, we interrogated archived correspondence and material associated with Griffith and Gill in the Osler Library History of Medicine (McGill University, Montreal, QC, Canada), Arthur E. Guedel Memorial Anesthesia Center (University of California, San Francisco, CA, USA), the Wood Library Museum of Anesthesiology (Schaumburg, IL, USA), the Anaesthesia Heritage Centre (London, UK), and the Wellcome Collection (London, UK). Further, we searched for information on the historical background of curare via Google, Ovid MEDLINE, Adam Matthew Explorer, Project MUSE, and Latin American History databases.We found seven letters. The first is a letter to Gill dated 2 June 1943 (Wood Library) and an earlier draft dated 2 June 1943 (Osler Library). In this letter, Griffith praises Gill's success in procuring curare and informs him of its usefulness in anesthesia. The second letter is a letter from Gill to Griffith dated 10 July 1943 (found affixed to a book that was donated to the Osler Library). In this letter, Gill congratulates Griffith and claims he foresaw curare's use in the operating room and predicts its routine use to produce muscle relaxation during surgery. The third letter is a letter to Griffith dated 17 April 1945 (Osler Library). In this correspondence, Gill disputes Squibb's claim that curare derives solely from C. tomentosum and asks Griffith to retract published statements on this point. The fourth letter is a letter to Gill dated 25 April 1945 (Osler Library), in which Griffith declines to retract and emphasizes that Gill receive credit for making curare available to medicine. The fifth letter is a letter to Griffith dated 24 May 1945 (Osler Library), in which Gill accepts Griffith's retraction decision and indicates negotiations with another drug company. The sixth letter is a letter to Griffith dated 11 July 1945 (Osler Library), in which Gill requests anesthesia morbidity and mortality data and continues to remonstrate against Squibb's claim of curare's botanical source. The seventh and final letter is to Gill and dated 21 July 1945 (Osler Library). In this letter, Griffith indicates the lack of morbidity and mortality information, mentions a new Squibb curare product, and cites data suggesting curare may exert dose-dependent CNS effects.These seven letters between Dr. H. Griffith and R. Gill reveal a professional relationship heretofore not appreciated. We discuss and consider these letters in the context of curare's remarkable history.

RéSUMé: Le Dr Harold R. Griffith et Richard C. Gill occupent une place importante dans l'histoire du curare. En 1938, Gill revient d'une expédition en Amazonie avec plus de 11 kg de curare. Après l'identification, par les scientifiques de E. R. Squibb & Sons, d'une source végétale (Chondrodendron tomentosum) et l'isolement d'un extrait stable de puissance uniforme (commercialisé sous le nom d'Intocostrin), Griffith l'administre en salle d'opération en 1942, montrant ses avantages et son innocuité. Dans cet article, nous résumons la correspondance entre Griffith et Gill, jusque-là peu appréciée, après avoir trouvé une lettre de Gill à Griffith glissée à l'intérieur de la quatrième de couverture d'un livre provenant d'une bibliothèque privée.À la suite de la découverte fortuite de cette lettre jusque-là inconnue, nous avons consulté la correspondance et les documents archivés associés à Griffith et Gill à la bibliothèque Osler History of Medicine (Université McGill, Montréal, QC, Canada), au centre Arthur E. Guedel Memorial Anesthesia Center (Université de Californie, San Francisco, CA, États-Unis), au Wood Library Museum of Anesthesiology (Schaumburg, IL, États-Unis), au Anaesthesia Heritage Centre (Londres, Royaume-Uni) et à la Wellcome Collection (Londres, Royaume-Uni). De plus, nous avons recherché des informations sur le contexte historique du curare via Google, Ovid MEDLINE, Adam Matthew Explorer, Project MUSE et dans les bases de données d'histoire de l'Amérique latine.Nous avons trouvé sept lettres. La première est une lettre à Gill datée du 2 juin 1943 (bibliothèque Wood) et une ébauche antérieure datée du 2 juin 1943 (bibliothèque Osler). Dans cette lettre, Griffith fait l'éloge du succès de Gill dans l'obtention du curare et l'informe de son utilité en anesthésie. La deuxième lettre est une lettre de Gill à Griffith datée du 10 juillet 1943 (trouvée collée dans un livre donné à la bibliothèque Osler). Dans cette lettre, Gill félicite Griffith et affirme qu'il avait pressenti l'utilisation du curare en salle d'opération et prédit son utilisation de routine pour produire une relaxation musculaire pendant la chirurgie. La troisième lettre est une lettre à Griffith datée du 17 avril 1945 (bibliothèque Osler). Dans cette missive, Gill conteste l'affirmation de Squibb selon laquelle le curare est exclusivement dérivé de C. tomentosum et demande à Griffith de se rétracter sur les déclarations publiées à ce sujet. La quatrième lettre est une lettre à Gill datée du 25 avril 1945 (bibliothèque Osler), dans laquelle Griffith refuse de se rétracter et insiste sur le fait que Gill soit crédité d'avoir mis le curare à la disposition de la médecine. La cinquième missive est une lettre à Griffith datée du 24 mai 1945 (bibliothèque Osler), dans laquelle Gill accepte la décision de Griffith de se rétracter et indique des négociations avec une autre compagnie pharmaceutique. La sixième lettre est une lettre à Griffith datée du 11 juillet 1945 (bibliothèque Osler), dans laquelle Gill demande des données concernant la morbidité et la mortalité liées à l'anesthésie et continue de protester contre l'affirmation de Squibb sur la source botanique du curare. La septième et dernière lettre est adressée à Gill et datée du 21 juillet 1945 (bibliothèque Osler). Dans cette lettre, Griffith indique le manque d'informations sur la morbidité et la mortalité, mentionne un nouveau produit à base de curare de Squibb et cite des données suggérant que le curare pourrait exercer des effets dose-dépendants sur le SNC.Ces sept lettres entre le Dr H. Griffith et R. Gill révèlent une relation professionnelle jusque-là peu appréciée. Nous discutons et considérons ces lettres dans le contexte de l'histoire remarquable du curare.

How does IVF conception affect pregnancy complications in an older cohort of women, at least 38 years of age? Study of a population database.

PURPOSE: To compare perinatal outcomes in in-vitro fertilization (IVF) pregnancies versus spontaneous conceptions in woman of advanced maternal age (AMA), and to evaluate the effect of increasing age on IVF pregnancies' outcomes. METHODS: A retrospective population-based cohort study including pregnant women who delivered between 2008-2014 in the US. First, we included women aged 38-43 years and compared those with IVF conceptions (cases) to women with spontaneous conceptions (controls). Thereafter, we compared IVF pregnancies in women aged 38-43 years to IVF pregnancies at < 38 years of age. Multivariate logistic regression was performed to compare both groups regarding pregnancy,delivery, and neonatal outcomes after adjusting for plausible confounders. RESULTS: Three hundred nine thousand five hundred sixty-seven pregnant women aged 38-43 years were identified, with 2,762 composing the IVF group, and 306,805 composing the control group. After adjusting for confounders, the IVF group had a higher risk of several adverse obstetrical outcomes, including hypertensive disorders of pregnancy (aOR 1.31,95%CI 1.06-1.62), gestational diabetes (aOR 1.26,95%CI 1.13-1.41),preterm delivery (aOR 1.45,95%CI 1.16-1.81), cesarean section (CS) (aOR 1.84,95%CI 1.55- 2.19),postpartum hemorrhage (aOR 1.68,95%CI 1.27- 2.24), and maternal infection (aOR 1.90,95%CI 1.31-2.77), with comparable neonatal outcomes. For the second analysis, 9712 IVF pregnancies were included (n = 6950 < 38 years, and n = 2762 ≥ 38 years). Women ≥ 38 years who underwent IVF were more likely to experience hypertensive disorders of pregnancy, CS, hysterectomy and blood transfusion, with comparable neonatal outcomes. CONCLUSION: IVF AMA pregnancies have a significant increase in myriad perinatal complications compared to spontaneous AMA pregnancies. Younger women undergoing IVF have mildly less complications than their older counterparts.

EIF1AX mutation in thyroid tumors: a retrospective analysis of cytology, histopathology and co-mutation profiles.

BACKGROUND: The EIF1AX mutation has been identified in various benign and malignant thyroid lesions, with a higher prevalence in poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma, especially when combined with RAS or TP53 mutation. However, data and clinical significance of EIF1AX mutations in thyroid nodules is still limited. We investigated the prevalence of EIF1AX mutations and co-mutations in cytologically indeterminate thyroid nodules at our institution. METHODS: A 5-year retrospective analysis was performed on surgically resected thyroid nodules with identified EIF1AX mutations on molecular testing with ThyroseqV3®. Mutation type and presence of co-mutations were correlated with histopathologic diagnosis and clinical characteristics. Histopathology diagnoses were subsequently categorized as benign, borderline, malignant or aggressive malignant (≥ 10% PDTC component). Chi-square test was used to compare the malignancy associations of the: 1) A113_splice mutation compared to non-A113_splice mutations 2) singular A113_splice mutations compared to singular non-A113_splice mutations. Fisher's Exact Test was used to determine the association of A113_splice mutation with aggressive malignancies compared to non-A113_splice mutations. A p value of 0.05 or less was considered statistically significant. RESULTS: Out of 1583 patients who underwent FNA, 621 had further molecular testing. 31 cases (5%) harbored EIF1AX mutations. Of these cases, 12 (38.7%) were malignant, 2 (6.5%) were borderline, and 17 (55%) were benign. 4/31 cases (13%) were aggressive malignant (≥ 10% PDTC component). The most prevalent mutation was the A113_splice mutation at the junction of intron 5 and exon 6 (48%). All other mutations, except one, were located at the N-terminal in exon 2. 7/31 cases (22.6%) harbored ≥ 1 co-mutation(s), including 4 RAS, 3 TP53, 1 TERT and 1 PIK3CA, with 86% of them being malignant. All 4 nodules with RAS co-mutations were malignant including one PDTC. CONCLUSION: Our study reports the largest cohort of EIF1AX mutations in Bethesda III/IV FNA samples with surgical follow-up to our knowledge. The presence of the EIF1AX mutation confers a 45.2% risk of malignancy (ROM) or borderline after surgery. However, the coexistence of EIF1AX mutations with other driver mutations such as RAS, TERT or TP53 conferred an 86% ROM. While 55% of thyroid nodules were benign at the time of surgery, the possible malignant transformation of these nodules, had they not been resected, is unknown. Finally, 13% of the nodules with EIF1AX mutations were aggressive with a significant PDTC component. These findings can further aid in clinical decisions for patients with thyroid nodules.

Postoperative hypotonia in a patient with stiff person syndrome: a case report and literature review.

PURPOSE: Stiff person syndrome (SPS), an autoimmune disease that manifests with episodic muscle rigidity and spasms, has anesthetic considerations because postoperative hypotonia may occur. This hypotonia has been linked to muscle relaxants and volatile anesthetics and may persist in spite of neostigmine administration and train-of-four (TOF) monitoring suggesting full reversal. We present a patient with SPS who experienced hypotonia following total intravenous anesthesia (TIVA), which was promptly reversed with sugammadex. These observations are considered in light of the relevant medical literature. CLINICAL FEATURES: A 46-yr-old female patient with SPS underwent breast lumpectomy and sentinel node biopsy. Anesthesia consisted of TIVA (propofol/remifentanil) with adjunctive administration of rocuronium 20 mg to obtain adequate intubating conditions. Despite return of the TOF ratio to 100% within 30 min, hypotonia was clinically evident at conclusion of surgery two hours later. Sugammadex 250 mg reversed residual muscle relaxation permitting uneventful extubation. A literature review identified six instances of postoperative hypotonia (TIVA, n = 3; volatile anesthetics, n = 3) in spite of neostigmine administration (n = 2) and TOF monitoring suggesting full reversal (n = 4). CONCLUSIONS: Patients with SPS may show hypotonia regardless of general anesthetic technique (TIVA vs inhalational anesthesia), which can persist despite recovery of the TOF ratio and may be more effectively reversed by a chelating agent than with an anticholinesterase. If general anesthesia is required, we suggest a cautious approach to administering muscle relaxants including using the smallest dose necessary, considering the importance of clinical assessment of muscle strength recovery in addition to TOF monitoring, and discussing postoperative ventilation risk with the patient prior to surgery.

RéSUMé: OBJECTIF: Le syndrome de la personne raide (SPR), une maladie auto-immune qui se manifeste par une rigidité musculaire et des spasmes épisodiques, requiert certaines considérations anesthésiques en raison du risque d'hypotonie postopératoire. Cette hypotonie a été liée à des myorelaxants et à des anesthésiques volatils et peut persister malgré l'administration de néostigmine et un monitorage du train-de-quatre (TDQ) suggérant une neutralisation complète. Nous présentons le cas d'une patiente atteinte de SPR qui a souffert d'hypotonie après une anesthésie intraveineuse totale (TIVA), laquelle a été rapidement neutralisée à l'aide de sugammadex. Ces observations sont examinées à la lumière de la littérature médicale pertinente. CARACTéRISTIQUES CLINIQUES: Une patiente de 46 ans atteinte de SPR a bénéficié d'une tumorectomie mammaire et d'une biopsie du ganglion sentinelle. L'anesthésie consistait en une TIVA (propofol/rémifentanil) avec administration d'appoint de 20 mg de rocuronium pour atteindre des conditions d'intubation adéquates. Malgré le retour du ratio de TdQ à 100 % dans les 30 minutes, l'hypotonie était cliniquement évidente à la fin de la chirurgie deux heures plus tard. L'administration de 250 mg de sugammadex a neutralisé la relaxation musculaire résiduelle, permettant une extubation sans incident. Une revue de la littérature a identifié six cas d'hypotonie postopératoire (TIVA, n = 3; anesthésiques volatils, n = 3) malgré l'administration de néostigmine (n = 2) et le monitorage du TdQ suggérant une neutralisation complète (n = 4). CONCLUSION: Les patients atteints de SPR peuvent présenter une hypotonie quelle que soit la technique d'anesthésie générale utilisée (TIVA vs anesthésie par inhalation), laquelle peut persister malgré la récupération du rapport de TdQ; cette hypotonie peut être plus efficacement neutralisée par un agent chélateur qu'avec un anticholinestérasique. Si une anesthésie générale est nécessaire, nous suggérons une approche prudente pour l'administration de myorelaxants, y compris l'utilisation de la plus petite dose nécessaire, la prise en compte de l'importance de l'évaluation clinique de la récupération de la force musculaire en plus du monitorage du TdQ, et la communication du risque de ventilation postopératoire au patient avant la chirurgie.

Advocating for prehabilitation for patients undergoing gynecology-oncology surgery.

Implementation of Enhanced Recovery After Surgery (ERAS) protocols in gynecology-oncology has resulted in improved perioperative outcomes. However, ERAS does not include preoperative interventions to address the comorbidities, malnutrition, weight loss/obesity, decreased functional capacity and high degree of anxiety and depression that are present in the gynecology-oncology patients. The amalgamation of these risk factors with the surgical stress response and chemoradiotherapy-related toxicities is associated with worse postoperative functional capacity and impaired quality of life. Not surprisingly, surgical-related decline in physical fitness is one of the most distressing symptoms reported by cancer patients. Restoring pre-treatment physical status and accelerating recovery can be done through prehabilitation. Prehabilitation is a multimodal program combining exercise, nutrition and psychological interventions to strengthen patients physically and mentally before surgery by addressing modifiable risk factors during the preoperative period thereby filling this existing gap. It has shown promising results in the colorectal and thoracic surgery populations. This paper elaborates on risk factors specific to the gynecology-oncology population, highlights selection criteria that should prompt referral to a prehabilitation program and advocates for the implementation of these programs in this population.

A Case Report of Systemic Intoxication Following Onabotulinum Toxin A Injections Into the Salivary Glands in a Patient With Spinal Muscular Atrophy Type 1.

BACKGROUND: Sialorrhea in spinal muscular atrophy (SMA) is caused by bulbar weakness, which is aggravated by low oromotor tone rather than saliva overproduction. Botulinum toxin (BTX) reduces sialorrhea by preventing acetylcholine release from the presynaptic secretory parasympathetic nerve terminals. An important adverse effect of BTX, as highlighted in its black box warning, is a systemic spread of BTX leading to botulismlike symptoms including dysphagia, muscle weakness, and death. These symptoms may be more pronounced in peripheral motor neuropathic disorder population such as SMA, whose neuromuscular junction (NMJ) is already dysfunctional. METHODS: We report a case of a 17-month-old boy with SMA type 1 following BTX injection for the treatment of sialorrhea. RESULTS: The boy developed severe generalized hypotonia, profound dysphagia, decreased airway clearance, and speech difficulty following BTX injection. Full gastric feeding was required. Pyridostigmine was started but with minimal effect. The patient experienced prolonged deleterious side effects of BTX, lasting upward of a year with very slow recovery of limb strengths and oromotor tone. CONCLUSIONS: NMJ dysfunction has been well described in SMA. BTX may exacerbate fragile NMJ function by inhibiting acetylcholine release at the presynaptic vesicles. As such, systematic intoxication of BTX can have far-reaching consequences in this population. A strong precaution and cautious weighing of efficacy and risk must be performed before utilizing BTX in the SMA population.

Older frail prehabilitated patients who cannot attain a 400 m 6-min walking distance before colorectal surgery suffer more postoperative complications.

INTRODUCTION: Recent efforts to prehabilitate intermediately frail and frail (Fried frailty criteria ≥2) elective colorectal cancer patients did not influence clinical nor functional outcomes. The objective of this secondary analysis was to describe the subset of intermediately frail and frail prehabilitated patients who could not attain a minimum 400 m (a prognostic cut-point used in other patient populations) 6-min walking distance (6MWD) before elective surgery. MATERIALS AND METHODS: Secondary analysis of a randomized controlled trial. Patients participated in multimodal prehabilitation at home and in-hospital for approximately four weeks before colorectal surgery. Primary outcome was incidence of postoperative complications within 30 days of hospital discharge. RESULTS: Sixty percent of the patients who participated in prehabilitation did not reach a minimum walking distance of 400 m in 6 min before surgery. Compared to the group that attained ≥400 m 6MWD (n = 19), the <400 m group (n = 28) were older, had higher percent body fat, lower physical function, lower self-reported physical activity, higher American Society of Anesthesiologists (ASA) classification, and twice as many were in critical need of a nutrition intervention at baseline. No group differences were observed regarding frailty status (P = 0.775). Sixty-one percent of the <400 m 6MWD group experienced at least one complication within 30 days of surgery compared to 21% in the ≥400 m group (P = 0.009). CONCLUSION: Several preoperative characteristics were identified in the <400 m 6MWD group that could be useful in screening and targeting future prehabilitative treatments. Future trials should investigate use of a 400 m standard for the 6MWD as a minimal treatment target for prehabilitation.

Effect of Multimodal Prehabilitation vs Postoperative Rehabilitation on 30-Day Postoperative Complications for Frail Patients Undergoing Resection of Colorectal Cancer: A Randomized Clinical Trial.

Importance: Research supports use of prehabilitation to optimize physical status before and after colorectal cancer resection, but its effect on postoperative complications remains unclear. Frail patients are a target for prehabilitation interventions owing to increased risk for poor postoperative outcomes. Objective: To assess the extent to which a prehabilitation program affects 30-day postoperative complications in frail patients undergoing colorectal cancer resection compared with postoperative rehabilitation. Design, Setting, and Participants: This single-blind, parallel-arm, superiority randomized clinical trial recruited patients undergoing colorectal cancer resection from September 7, 2015, through June 19, 2019. Patients were followed up for 4 weeks before surgery and 4 weeks after surgery at 2 university-affiliated tertiary hospitals. A total of 418 patients 65 years or older were assessed for eligibility. Of these, 298 patients were excluded (not frail [n = 290], unable to exercise [n = 3], and planned neoadjuvant treatment [n = 5]), and 120 frail patients (Fried Frailty Index,≥2) were randomized. Ten patients were excluded after randomization because they refused surgery (n = 3), died before surgery (n = 3), had no cancer (n = 1), had surgery without bowel resection (n = 1), or were switched to palliative care (n = 2). Hence, 110 patients were included in the intention-to-treat analysis (55 in the prehabilitation [Prehab] and 55 in the rehabilitation [Rehab] groups). Data were analyzed from July 25 through August 21, 2019. Interventions: Multimodal program involving exercise, nutritional, and psychological interventions initiated before (Prehab group) or after (Rehab group) surgery. All patients were treated within a standardized enhanced recovery pathway. Main Outcomes and Measures: The primary outcome included the Comprehensive Complications Index measured at 30 days after surgery. Secondary outcomes were 30-day overall and severe complications, primary and total length of hospital stay, 30-day emergency department visits and hospital readmissions, recovery of walking capacity, and patient-reported outcome measures. Results: Of 110 patients randomized, mean (SD) age was 78 (7) years; 52 (47.3%) were men and 58 (52.7%) were women; 31 (28.2%) had rectal cancer; and 87 (79.1%) underwent minimally invasive surgery. There was no between-group difference in the primary outcome measure, 30-day Comprehensive Complications Index (adjusted mean difference, -3.2; 95% CI, -11.8 to 5.3; P = .45). Secondary outcome measures were also not different between groups. Conclusions and Relevance: In frail patients undergoing colorectal cancer resection (predominantly minimally invasive) within an enhanced recovery pathway, a multimodal prehabilitation program did not affect postoperative outcomes. Alternative strategies should be considered to optimize treatment of frail patients preoperatively. Trial Registration: ClinicalTrials.gov identifier: NCT02502760.