Local anaesthesia for pain control in first trimester surgical abortion.

BACKGROUND: Abortions prior to 14 weeks are among the most common outpatient surgical procedures performed on people capable of becoming pregnant. Various methods have been used to control pain; however, many people still experience pain with the procedure. OBJECTIVES: To evaluate the benefits and harms of local anaesthesia given for pain control during surgical abortion at less than 14 weeks' gestation. SEARCH METHODS: We searched CENTRAL (Ovid EBM Reviews), MEDLINE (Ovid), Embase, POPLINE, and Google Scholar to December 2022 for randomized controlled trials of pain control in surgical abortion at less than 14 weeks' gestation using suction aspiration. We searched the reference lists of related reviews and articles. SELECTION CRITERIA: We selected effectiveness and comparative effectiveness randomized controlled trials that studied local anaesthesia with common local anaesthetics and administration routes given for pain control in surgical abortion at less than 14 weeks' gestation using uterine aspiration. Outcomes included intraoperative pain, patient satisfaction, and adverse events. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We computed mean differences (MD) with 95% confidence intervals (CI) for continuous variables reporting a mean. We assessed the certainty of evidence using GRADE. MAIN RESULTS: Thirteen studies with 1992 participants met the inclusion criteria. Due to heterogeneity of interventions, we could not pool more than two studies for any outcome. We used 13 mm improvement on a visual/verbal analogue scale to indicate a clinically meaningful difference in pain with surgical abortion (pain with dilation, aspiration, or during procedure). Based on type of pain control, we divided studies into three groups. Paracervical block (PCB) effectiveness trials A 20 mL 1% lidocaine PCB reduced pain with dilation (MD -37.00, 95% CI -45.64 to -28.36), and aspiration (MD -26.00, 95% CI -33.48 to -18.52) compared to a sham PCB (1 RCT, 120 participants; high-certainty evidence). A PCB with 14 mL of 1% chloroprocaine resulted in a slight reduction in pain with aspiration compared to a PCB with normal saline injected at two or four sites (MD -1.50, 95% CI -2.45 to -0.55; 1 RCT, 79 participants; high-certainty evidence). PCB comparative effectiveness trials An ultracaine PCB probably results in little to no clinically meaningful difference in pain during procedure compared to topical cervical lidocaine spray (median 1 point higher, interquartile range (IQR) 0 to 3; P < 0.001; 1 RCT, 48 participants; moderate-certainty evidence). A 1000 mg dose of intravenous paracetamol probably does not decrease pain as much as ultracaine PCB during procedure (median 2 points higher, IQR 1 to 3; P < 0.001; 1 RCT, 46 participants; moderate-certainty evidence). Various local anaesthetics in PCB comparative effectiveness trials A 10 mL buffered 2% lidocaine PCB probably does not result in a clinically meaningful difference in pain with dilation compared to a plain lidocaine PCB (MD -0.80, 95% CI -0.89 to -0.71; 1 RCT, 167 participants; moderate-certainty evidence). A buffered lidocaine PCB probably does not result in a clinically meaningful difference in pain with aspiration compared to plain lidocaine PCB (MD -0.57, 95% CI -1.01 to -0.06; 2 RCTs, 291 participants; moderate-certainty evidence). Non-PCB local anaesthesia or PCB technique effectiveness trials PCB: waiting versus no waiting Waiting three to five minutes between 1% lidocaine PCB injection and dilation probably does not result in a clinically meaningful difference in pain with dilation compared to not waiting (MD -0.70, 95% CI -1.23 to -0.17; 2 RCTs, 357 participants; moderate-certainty evidence). Topical cervical analgesia Topical 10 mL 2% lignocaine gel probably does not result in a clinically meaningful difference in pain with aspiration compared to KY Jelly (MD -0.87, 95% CI -1.60 to -0.14; 1 RCT, 131 participants; moderate-certainty evidence). In participants who also received a PCB, 20 mg topical cervical lidocaine spray probably does not result in a clinically meaningful difference in pain during the procedure compared to two pumps of normal saline spray (median -1 point, IQR -2 to -1; P < 0.001; 1 RCT, 55 participants; moderate-certainty evidence). Intravenous paracetamol 1000 mg compared to two pumps of cervical lidocaine spray probably does not results in a clinically meaningful difference in pain procedure (median 1 point, IQR -2 to 2; P < 0.001; 1 RCT, 48 participants; low-certainty evidence). Non-PCB local anaesthesia or PCB technique comparative effectiveness trials Depth of PCB The evidence suggests that a 3-cm deep PCB probably does not result in a clinically meaningful difference in pain with aspiration compared to a 1.5-cm deep PCB (MD -1.00, 95% CI -1.09 to -0.91; 2 RCTs, 229 participants; low-certainty evidence). PCB: four sites versus two sites A two-site (4-8 o'clock) 20 mL 1% lidocaine PCB does not result in a clinically meaningful difference in pain with dilation compared to a four-site (2-4-8-10 o'clock) PCB (MD 8.60, 95% CI 0.69 to 16.51; 1 RCT, 163 participants; high-certainty evidence). Overall, participants reported moderately high satisfaction with pain control and studies reported few adverse events. AUTHORS' CONCLUSIONS: Evidence from this updated review indicates that a 20 mL 1% plain lidocaine PCB decreases pain during an abortion procedure. Evidence supports forgoing buffering lidocaine and a wait time between PCB injection and cervical dilation. A 1.5-cm deep injection as opposed to a 3-cm deep injection is sufficient. A two-site PCB injection as opposed to a four-site injection has similar effectiveness. Topical cervical anaesthesia (10 mL 2% lignocaine gel or 20 mg topical cervical lidocaine spray) as compared to placebo did not decrease pain based on moderate-certainty evidence, but then when compared to PCB, pain control was similar. Due to this inconsistency in evidence regarding the effectiveness of topical anaesthesia, its routine use is presently not supported. This review did not include studies of pain management with conscious sedation but, based on the results of our prior Cochrane review and the 2022 WHO guidelines, we recommend that the option of combination of pain management using conscious sedation plus PCB and non-steroidal anti-inflammatory drugs should be offered where conscious sedation is available as it further decreases pain.

First and Second-Trimester Surgical Abortion Providers and Services in 2019: Results From the Canadian Abortion Provider Survey.

OBJECTIVE: Our objective was to explore the workforce and clinical care of first and second-trimester surgical abortion (FTSA, STSA) providers following the publication of the updated Society of Obstetricians and Gynaecologists of Canada (SOGC) surgical abortion guidelines. METHODS: We conducted a national, cross-sectional, online, self-administered survey of physicians who provided abortion care in 2019. This anonymized survey collected participant demographics, types of abortion services, and characteristics of FTSA and STSA clinical care. Through healthcare organizations using a modified Dillman technique, we recruited from July to December 2020. Descriptive statistics were generated by R Statistical Software. RESULTS: We present the data of 222 surgical abortion provider respondents, of whom 219 provided FTSA, 109 STSA, and 106 both. Respondents practiced in every Canadian province and territory. Most were obstetrician-gynaecologists (56.8%) and family physicians (36.0%). The majority of FTSA and STSA respondents were located in urban settings, 64.8% and 79.8%, respectively, and more than 80% practiced in hospitals. More than 1 in 4 respondents reported <5 years' experience with surgical abortion care and 93.2% followed SOGC guidelines. Noted guideline deviations included that prophylactic antibiotic use was not universal, and more than half of respondents used sharp curettage in addition to suction. Fewer than 5% of STSA respondents used mifepristone for cervical preparation. CONCLUSION: The surgical abortion workforce is multidisciplinary and rejuvenating. Education, training, and practice support, including SOGC guideline implementation, are required to optimize care and to ensure equitable FTSA and STSA access in both rural and urban regions. GESTATIONAL AGE NOTATION: weeks, weeks' gestation, gestational age (GA), e.g., 116 weeks.

Experience of stigma and harassment among respondents to the 2019 Canadian abortion provider survey.

OBJECTIVE: We conducted a national survey to assess the experiences of stigma and harassment among physicians and nurse practitioners providing abortions and abortion service administrators in Canada. STUDY DESIGN: We conducted an exploratory, cross-sectional, national, anonymized, online survey between July and December 2020. Subsections of the survey explored stigma and harassment experienced by respondents, including the 35-item Revised Abortion Providers Stigma Scale and open-ended responses. We analyzed the quantitative data to generate descriptive statistics and employed a reflexive thematic analysis to interpret open-ended responses. RESULTS: Three hundred fifty-four participants started the stigma and harassment section of the survey. Among low-volume clinicians (<30 abortions/year, 60%, n = 180) 8% reported harassment; 21% among higher volume clinicians (≥30 abortions/year, 40%, n = 119) and 47% among administrators (n = 39), most commonly picketing. The mean stigma score was 67.8 (standard deviation 17.2; maximum score 175). Our qualitative analysis identified five themes characterizing perceptions of stigma and harassment: concerns related to harassment from picketing, protestors, and the public; wanting protestor "bubble zones"; aiming to be anonymous to avoid being a target; not providing an abortion service; but also witnessing a safe and positive practice environment. CONCLUSIONS: Being a low-volume clinician compared to higher volume clinician and administrator appears to be associated with less harassment. Clinicians providing abortion care in Canada reported mid-range abortion-related stigma scores, and expressed strong concerns that stigma interfered with their abortion provision. Our results indicate that further de-stigmatization and protection of abortion providers in Canada is needed through policy and practice interventions including bubble zones. IMPLICATIONS: While Canadian abortion care clinicians and administrators reported relatively low incidence of harassment, our results indicate that they are concerned about stigma and harassment. However, as this was an exploratory survey, these data may not be representative of all Canadian abortion providers. Our data identify a need to support abortion clinicians and to bolster protections for dedicated abortion services.

Development and pilot testing of the 2019 Canadian Abortion Provider Survey.

BACKGROUND: Substantial changes in abortion care regulations, available medications and national clinical practice guidelines have occurred since a 2012 national Canadian Abortion Provider Survey (CAPS). We developed and piloted the CAPS 2019 survey instrument to explore changes of the abortion provider workforce, their clinical care as well as experiences with stigma and harassment. METHODS: We undertook development and piloting in three phases: (1) development of the preliminary survey sections and questions based on the 2012 survey instrument, (2) content validation and feasibility of including certain content aspects via a modified Delphi Method with panels of clinical and research experts, and (3) pilot testing of the draft survey for face validity and clarity of language; assessing usability of the web-based Research Electronic Data Capture platform including the feasibility of complex skip pattern functionality. We performed content analysis of phase 2 results and used a general inductive approach to identify necessary survey modifications. RESULTS: In phase 1, we generated a survey draft that reflected the changes in Canadian abortion care regulations and guidelines and included questions for clinicians and administrators providing first and second trimester surgical and medical abortion. In phase 2, we held 6 expert panel meetings of 5-8 participants each representing clinicians, administrators and researchers to provide feedback on the initial survey draft. Due to the complexity of certain identified aspects, such as interdisciplinary collaboration and interprovincial care delivery differences, we revised the survey sections through an iterative process of meetings and revisions until we reached consensus on constructs and questions to include versus exclude for not being feasible. In phase 3, we made minor revisions based on pilot testing of the bilingual, web-based survey among additional experts chosen to be widely representative of the study population. Demonstrating its feasibility, we included complex branching and skip pattern logic so each respondent only viewed applicable questions based on their prior responses. CONCLUSIONS: We developed and piloted the CAPS 2019 survey instrument suitable to explore characteristics of a complex multidisciplinary workforce, their care and experience with stigma on a national level, and that can be adapted to other countries.

Telemedicine for First-Trimester Medical Abortion in Canada: Results of a 2019 Survey.

Introduction: Telemedicine has the potential to improve abortion access disparities in Canada. We aimed to explore the provision of telemedicine for first-trimester medical abortion and related barriers in 2019. Methods: We conducted a national, cross-sectional, anonymized, web-based survey of clinicians who provided abortion care in 2019 in Canada. We distributed our survey through professional health organizations to maximize identification of possible eligible respondents and used a modified Dillman technique to foster responses. Questions elicited provider demographics, clinical characteristics, including telemedicine first-trimester medical abortion and perceived related barriers. Descriptive statistics were analyzed using R software. Results: Among 465 respondents, 388 reported providing first-trimester medical abortion across Canada; 44.0% reported experience using telemedicine for some components of care: 49.3% of primary care clinicians and 28.7% of specialists. Telemedicine was used for initial consultation (86.0%), prescription (82.2%), or follow-up (92.2%). The median percentage of telemedicine providers' patients who underwent a dating ultrasound was 90.0. The majority usually followed up with patients through quantitative human chorionic gonadotropin (hCG) (84.2%). Seventy-eight percent perceived barriers to telemedicine; the most common being inability to confirm gestational age with ultrasound (43.0%), and lack of provincial telemedicine abortion fee code to pay practitioners (30.2%), timely access to serum hCG testing (24.6%), and nearby emergency services (23.3%). Discussion: In 2019, fewer than half of respondents reported providing some aspects of first-trimester medical abortion through telemedicine and the majority perceived barriers. Our results can inform knowledge translation activities to reduce barriers and increase telemedicine abortion care in Canada.

Abortion services and providers in Canada in 2019: results of a national survey.

BACKGROUND: Since 2016, abortion care has undergone several important changes, particularly related to the provision of medical abortion using mifepristone. We aimed to document characteristics of the abortion care workforce in Canada after the update of clinical practice guidelines of mifepristone use for medical abortion. METHODS: We conducted a national, web-based, anonymized, bilingual (English/French) survey. We collected demographics and clinical care characteristics of physicians and nurse practitioners who provided abortion care in 2019. Between July and December 2020, we distributed the survey through professional organizations, including The College of Family Physicians of Canada and The Society of Obstetricians and Gynaecologists of Canada. We present descriptive statistics. RESULTS: Overall, 465 respondents representing all 10 provinces and 3 territories in Canada completed the survey. Of these, 388 (83.4%), including 30 nurse practitioners, provided first-trimester medical abortion, of which 350 (99.4%) used mifepristone. Two hundred and nineteen (47.1%) respondents provided first-trimester surgical abortion, 109 (23.4%) provided second-trimester surgical abortion and 115 (24.7%) provided second- or third-trimester medical abortion. Half of respondents reported fewer than 5 years of experience with any abortion care. Respondents reported providing a total of 48 509 abortions in 2019, including 32 345 (66.7%) first-trimester surgical abortions and 13 429 (27.7%) first-trimester medical abortions. In Quebec, only 1918 (12.5%) of reported abortions were first-trimester medical abortions. Primary care providers provided 34 540 (71.2%) of the total abortions. First-trimester medical abortions represented 44.4% (n = 2334) of all abortions in rural areas, as opposed to 25.6% (n = 11 067) in urban areas. INTERPRETATION: The increased availability of medical abortion facilitates abortion access, especially in primary care and rural settings, and where surgical abortion is not available. Rejuvenation of the workforce is a critical contributor to equitable access to abortion services.

Safety Data in Patients with Autoimmune Diseases during Treatment with High Doses of Vitamin D3 According to the "Coimbra Protocol".

BACKGROUND: In 2013, the group of Cicero Coimbra, Brazil, reported the clinical efficacy of high doses of vitamin D3 in patients suffering from autoimmune skin disorders ("Coimbra protocol", CP). However, hypercalcemia and the subsequent impaired renal function may be major concerns raised against this protocol. METHODS: We report for the first time for a broad spectrum of autoimmune diseases in 319 patients (mean age (±SD) 43.3 ± 14.6 years, 65.5% female, 34.5% male) safety data for high doses of orally applied vitamin D3 (treatment period: up to 3.5 years) accompanied by a strict low-calcium diet and regular daily fluid intake of at least 2.5 L. RESULTS: Mean vitamin D3 dose was 35,291 ± 21,791 IU per day. The measurement of more than 6100 single relevant laboratory parameters showed all mean values (±SD) within the normal range for total serum calcium (2.4 ± 0.1 mmol/L), serum creatinine (0.8 ± 0.2 mg/dL), serum creatinine associated estimated GFR (92.5 ± 17.3 mL/min), serum cystatin C (0.88 ± 0.19 mg/L), serum TSH (1.8 ± 1 mIU/L), and for 24 h urinary calcium secretion (6.9 ± 3.3 mmol/24 h). We found a very weak relationship between the dosage of oral vitamin D3 and the subsequent calcium levels, both in serum and in urinary excretion over 24 h, respectively. CONCLUSIONS: Our data show the reliable safety of the CP in autoimmune patients under appropriate supervision by experienced physicians.

Provision of first-trimester medication abortion in 2019: Results from the Canadian abortion provider survey.

OBJECTIVE: To explore the Canadian first-trimester medication abortion (MA) workforce and their clinical care following the introduction of mifepristone in 2017, updated national clinical practice guidelines and government approval of nurse practitioners (NPs) as first-trimester MA providers. STUDY DESIGN: We conducted a national, self-administered, cross-sectional survey of abortion providers in 2019. Our bilingual (French/English) survey collected information on demographics, abortion number, and clinical care characteristics. The true number of abortion providers is unknown thus we cannot calculate a survey response rate. To maximize identification of possibly eligible respondents, we widely distributed the survey between July and December 2020 through health professional organizations, using a modified Dillman technique. We used descriptive statistics to characterize the workforce and clinical practices. RESULTS: Four-hundred-sixty-five clinicians responded, of whom 388 provided first-trimester MA. Physicians (n = 358) and NPs (n = 30) reported providing 13,429 first-trimester MAs in 2019 which represented 27.7% of all reported abortions in the survey. The majority of first-trimester MA respondents were primary care physicians (n = 245, 63.1%), had less than five years' experience (n = 223, 61.3%) and practiced outside of hospitals (n = 228, 66.5%). Forty-three percent (n = 165) practiced rurally, and 44.0% (n = 136) used telemedicine for some abortion care. Ninety-nine percent (n = 350) used a guideline-recommended mifepristone/misoprostol regimen while 14.5% (n = 51) sometimes used methotrexate. Patients most commonly received mifepristone/misoprostol at community pharmacies (median 100.0%; interquartile range 50.0%-100.0%). CONCLUSION: Our results suggest that there are many new first-trimester MA providers, an increase in the proportion of MAs since 2012 and a shift to primary care settings. Respondents widely adopted mifepristone. IMPLICATIONS STATEMENT: Our results highlight that, following mifepristone introduction, many new primary care practitioners started providing first-trimester medication abortion throughout Canada, including the first non-physicians. This increased access to abortion particularly in rural and underserved communities. These results could inform future directions in policy, guidelines, and abortion access initiatives.

Second- and Third-Trimester Medical Abortion Providers and Services in 2019: Results From the Canadian Abortion Provider Survey.

OBJECTIVES: Mifepristone became available in Canada in 2017. Updated national guidelines recommend its off-label use for second/third-trimester medical abortion (STMA/TTMA) by labour induction. The objective of this study was to explore STMA/TTMA provision in Canada and the role of mifepristone. METHODS: We conducted a national, cross-sectional, web-based, self-administered, anonymized survey, available in English and French. The survey was distributed through health professional organizations and recruited physicians who provided abortion care in 2019. We used a modified Dillman technique to maximize participation. The survey included sections on workforce and clinical care, including mifepristone use. We used R statistical software to produce descriptive statistics. RESULTS: Four hundred sixty-five clinicians responded to the survey, of whom 112 reported providing STMA and 63, TTMA, for a total of 115 respondents providing at least 1 of the 2 services. Two-thirds of respondents were general obstetrician-gynaecologists or family physicians and the remainder were maternal-fetal medicine subspecialists. The majority (64.7%) provided STMA/TTMA in an academic hospital, and 59.4% performed fewer than 5 STMAs (maximum 50) and 76.1%, fewer than 5 TTMA (maximum 15) in 2019. Fifty-nine percent of respondents reported having used mifepristone/misoprostol for STMA. Among mifepristone users, 48.6% used it for TTMA. Most required an indication beyond patient request to provide STMA/TTMA (82.1%/95.5%). CONCLUSIONS: STMA/TTMA care is provided by multiple (sub-) specialties, and mifepristone has not yet been universally implemented. Our results will inform knowledge translation activities aimed at facilitating collaboration between STMA/TTMA providers and health policy and service delivery leaders and will further increase mifepristone use for STMA/TTMA in Canada.

Antimicrobial properties of phytohormone (gibberellins) against phytopathogens and clinical pathogens.

The in vitro antimicrobial potential of physiologically active diterpenoid plant-derived gibberellins (gibberellic acids; GAs) was tested on microbial pathogens of significance to plant and human health. The racemic enantiomer GA3 produced varying inhibitory effects against a wide range of plant host disease causal agents (phytopathogens) comprising fungi, oomycetes and bacteria. The results showed that GA3 effected either strong growth arrest of phytopathogenic fungi or holistic biocidal effects on oomycete and phytopathogenic fungi at higher concentration (>10-50 mM) and increased hyphal extension growth when the concentration of GA3 was lowered (<10-0.1 mM). When human clinical pathogenic bacteria cohorts were challenged with gibberellin enantiomers, viz GA1, GA4, GA5, GA7, GA9 and GA13 (50 mM), employing Kirby-Bauer disc bioassay methods for assessment of their efficacies, no inhibitory effect was seen with gibberellin enantiomers, viz GA1, GA3, GA5 and GA13, while GA4 inhibited all human clinical bacterial organisms examined, with GA7 and GA9 showing limited activity. The antibiotic effects of enantiomeric diterpenoid phytohormones evinced in our preliminary study raise prospects for further studies to fully examine their potential therapeutic value for human healthcare and their compliance with cytotoxicity and other ethical considerations in the future.

A discussion on the 'dispensable' amino acids.

PURPOSE OF REVIEW: Recently, the concept of dietary dispensable amino acids has been increasingly challenged, as more indirect and direct (experimental) evidence has pointed to the need for them in the diet during specific life stages or disease states. Here, we discuss the classification of amino acids, methods to assess the needs for dispensable amino acids with experimental evidence from our recent studies, and highlight the role of specific dispensable amino acids in metabolism and health. RECENT FINDINGS: There exist differences among the dispensable amino acids to act as effective nitrogen sources in humans. Glycine, a dispensable amino acid is conditionally indispensable in later stages of human pregnancy. SUMMARY: The so-called 'dispensable' amino acids are quantitatively nearly 75% of the daily protein needs in humans. In certain life-stages and diseases, there is a dietary demand for the dispensable amino acids. Future well-designed studies are required to identify the dietary demand for these amino acids, which will certainly be useful for dietary management in specific diseases and to maintain health across all life-stages.

The perspective of Canadian health care professionals on abortion service during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic and pandemic response created novel challenges for abortion services. Canada was uniquely positioned to transition to telemedicine because internationally common restrictions on abortion medication were removed before the pandemic. OBJECTIVE: We sought to characterize the experiences of abortion health care professionals in Canada during the COVID-19 pandemic and the impact of the pandemic response on abortion services. METHODS: We conducted a sequential mixed methods study between July 2020 and January 2021. We invited physicians, nurse practitioners and administrators to participate in a cross-sectional survey containing an open-ended question about the impact of the pandemic response on abortion care. We employed an inductive codebook thematic analysis, which informed the development of a second, primarily quantitative survey. RESULTS: Our initial survey had 307 respondents and our second had 78. Fifty-three percent were family physicians. Our first survey found respondents considered abortion access essential. We identified three key topicss: access to abortion care was often maintained despite pandemic-related challenges (e.g. difficulty obtaining tests, additional costs); change of practice to low-touch medication abortion care and provider perceptions of patient experience, including shifting demand, telemedicine acceptability and increased rural access. The second survey indicated uptake of telemedicine medication abortion among 89% of participants except in Quebec, where regulations meant procedures were nearly exclusively surgical. Restrictions did not delay care according to 76% of participants. CONCLUSIONS: Canadian health care professionals report their facilities deemed abortion an essential service. Provinces and territories, except Quebec, described a robust pandemic transition to telemedicine to ensure access to services. PODCAST: An accompanying podcast is available in the Supplementary Data, in which the authors Dr Madeleine Ennis and Kate Wahl discuss their research on how family planning care and access to abortion services have changed during the COVID-19 pandemic.

Access to abortion care was challenged by the response to COVID-19. Canada had fewer restrictions on medical abortion than many other countries when the pandemic began. The goal of this study was to describe the experiences of health care practitioners providing abortion in Canada and the impact of the pandemic and the pandemic response measures on abortion services. We conducted two surveys of physicians, nurse practitioners and administrators between July 2020 and January 2021. Most of the health care practitioners who participated reported that medical and surgical abortion care were essential and that, except in the province of Quebec, there was a rapid transition to virtual telemedicine care for first trimester abortions. Several practitioners said that virtual care made abortion more accessible. Other practitioners reported that it was challenging to order certain tests, access operating room facilities or make referrals for late second trimester cases. Practitioners felt that patients had strong fears about COVID-19 exposure and reported that limited contraception access was increasingly a reason for seeking abortion care. The results of the study suggested that abortion was considered essential and that the pandemic instigated a transition to virtual care in all provinces and territories except Quebec.

Glycine, a Dispensable Amino Acid, Is Conditionally Indispensable in Late Stages of Human Pregnancy.

BACKGROUND: Recently, we showed that there are higher protein, lysine, and phenylalanine requirements in late stages of pregnancy compared with early stages. Animal studies have suggested an increased dietary need for specific dispensable amino acids in pregnancy; whether such a need exists in human pregnancies is unknown. OBJECTIVE: The objective of the current study was to examine whether healthy pregnant women at midgestation (20-29 wk) and late gestation (30-40 wk) have a dietary demand for glycine, a dispensable amino acid, using the indicator amino acid oxidation method and measurement of plasma 5-oxoproline concentrations. METHODS: Seventeen healthy women (aged 26-36 y) randomly received different test glycine intakes (range: 5-100 mg·kg-1·d-1) during each study day in midgestation (∼26 wk, n = 17 observations in 9 women) and late gestation (∼35 wk, n = 19 observations in 8 women). Diets were isocaloric with energy at 1.7 × resting energy expenditure. Protein was given as a crystalline amino acid mixture based on egg protein composition at current estimated average requirement (EAR; 0.88 g·kg-1·d-1). Breath samples were collected at baseline and isotopic steady state to measure oxidation of L-[1-13C]phenylalanine to 13CO2 (F13CO2). Plasma was collected at the sixth hour of the study day. Linear regression crossover analysis and simple linear regression were used to assess responses in F13CO2 and plasma 5-oxoproline concentrations to different glycine intakes. RESULTS: No statistically significant responses were observed in midgestation. However, in late gestation, lower glycine intakes resulted in higher rates of F13CO2 (suggesting low protein synthesis) with a breakpoint for phenylalanine oxidation at >37 mg glycine·kg-1·d-1 and higher plasma 5-oxoproline (suggesting low glycine availability) with a breakpoint >27 mg glycine·kg-1·d-1. CONCLUSIONS: The findings suggest that glycine should be considered a "conditionally" indispensable amino acid during late gestation, especially when protein intakes are at 0.88 g·kg-1·d-1, the current EAR. This trial was registered at clinicaltrials.gov as NCT02149953.

Histamine receptors and COVID-19.

OBJECTIVE: Reports that the over-the-counter histamine H2 receptor antagonist famotidine could help treat the novel coronavirus disease (COVID-19) appeared from April 2020. We, therefore, examined reports on interactions between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and histamine receptor antagonists. METHODS: A systematic literature search was performed by 19 September 2020, and updated on 28 October 2020, in PubMed, Scopus, Cochrane Library and Google Scholar using (COVID-19 OR coronavirus OR SARS-CoV-2) AND (histamine antagonist OR famotidine OR cimetidine). ClinicalTrials.gov was searched for COVID-19 and (famotidine or histamine). RESULTS: Famotidine may be a useful addition in COVID-19 treatment, but the results from prospective randomized trials are as yet awaited. Bioinformatics/drug repurposing studies indicated that, among several medicines, H1 and H2 receptor antagonists may interact with key viral enzymes. However, in vitro studies have to date failed to show a direct inhibition of famotidine on SARS-CoV-2 replication. CONCLUSIONS: Clinical research into the potential benefits of H2 receptor antagonists in managing COVID-19 inflammation began from a simple observation and now is being tested in multi-centre clinical trials. The positive effects of famotidine may be due to H2 receptor-mediated immunomodulatory actions on mast cell histamine-cytokine cross-talk, rather than a direct action on SARS-CoV-2.

Dietary Aromatic Amino Acid Requirements During Early and Late Gestation in Healthy Pregnant Women.

BACKGROUND: Phenylalanine and tyrosine (referred to as total aromatic amino acids; TAAs) are essential for protein synthesis, and are precursors for important catecholamines. Current estimated average requirement (EAR) recommendations for TAA during pregnancy are 36 mg·kg-1·d-1, and has not been experimentally determined. OBJECTIVES: The aim was to determine TAA requirements (dietary phenylalanine in the absence of tyrosine) during early and late gestation using the indicator amino acid oxidation (IAAO, with L-[1-13C]leucine) technique. METHODS: Nineteen healthy pregnant women (age 22-38 y) were studied at a range of phenylalanine intakes (5 to 100 mg·kg-1·d-1) in early (13-19 wk) and/or late (33-39 wk) pregnancy for a total of 51 study days. Graded test intakes were provided as 8 hourly isonitrogenous and isocaloric meals. Breath samples were collected for 13C enrichment analysis on an isotope ratio mass spectrometer. A plasma sample was collected and analyzed for phenylalanine and tyrosine concentrations on an amino acid analyzer. The TAA requirement in early and late pregnancy was calculated using 2-phase linear regression crossover analysis that identified breakpoints in 13CO2 production (the requirement) in response to phenylalanine intakes. RESULTS: TAA requirement during early pregnancy was 44 mg·kg-1·d-1 (95% CI: 28.3, 58.8) and during late pregnancy was 50 mg·kg-1·d-1 (95% CI: 36.1, 63.1). In early and late pregnancy, plasma phenylalanine and tyrosine concentrations rose linearly in response to graded phenylalanine intakes. CONCLUSIONS: Our results suggest that the current EAR of 36 mg·kg-1·d-1 for TAAs is underestimated. When compared with results previously determined in nonpregnant adults, early pregnancy requirements were similar (43 compared with 44 mg·kg-1·d-1, respectively). During late pregnancy, a 14% higher TAA requirement was observed when compared with early pregnancy. The results from this study have potential implications for creating gestation stage-specific TAA recommendations.

Impact of enteral arginine supplementation on lysine metabolism in humans: A proof-of-concept for lysine-related inborn errors of metabolism.

Patients with lysine-related inborn errors of metabolism (pyridoxine-dependent epilepsy [PDE] and glutaric aciduria type 1 [GA1]), follow a lysine-restricted diet with arginine-fortified lysine-free amino acid formula and additional oral arginine supplementation as a newer therapy for PDE. The rationale of arginine supplementation is based on arginine's ability to compete with lysine transport across cell membranes via shared transporter systems. Adequate doses of arginine required to competitively inhibit enteral lysine uptake has not been studied in humans This proof-of-concept study investigates the effect of incremental enteral arginine doses on whole-body lysine oxidation using an in vivo stable isotope tracer, L-[1-13 C] lysine, in healthy humans. Five healthy men completed six study days each consuming one dose of l-arginine HCl per study day; range = 50-600 mg/kg/d. Lysine intake was at DRI (30 mg/kg/d). Breath samples were analysed for L-[1-13 C] lysine oxidation to 13 CO2 using an isotope ratio mass spectrometer. Plasma amino acid concentrations were analysed using an amino acid analyser. Increasing doses of l-arginine HCl caused a linear decrease in whole-body lysine oxidation. Plasma arginine concentration increased, and plasma lysine concentration decreased below normal range with high arginine intakes. We provide the first empirical evidence of arginine-lysine antagonism in response to increasing oral arginine doses. Results suggest 300-600 mg/kg/d of l-arginine HCl and lysine intake restricted to DRI is needed to reduce enteral lysine uptake and systemic lysine oxidation. This could potentially lead to a recommended dose for arginine in lysine-related inborn errors of metabolism.

Histamine pharmacology: from Sir Henry Dale to the 21st century.

Histamine has been one of the most studied substances in medicine, playing a major role in diverse (patho)physiological processes. It elicits its multifaceted modulatory functions by activating four types of GPCRs, designated as H1-4 . Despite the heterogeneity and the complexity of histamine receptor pharmacology, many discoveries over the past 100 years resulted in the development of H1 antihistamines and H2 -targeting 'blockbuster' therapeutics for the management of allergies and gastrointestinal disorders respectively. Recently, a first-in-class H3 inverse agonist was approved for the treatment of narcolepsy, whereas H4 antagonists are under clinical evaluation for their potential therapeutic exploitation in immune-related diseases. This review critically presents the past successes and drawbacks in histamine research, complemented by the modern conceptual innovations in molecular and receptor pharmacology. It targets both young and experienced researchers in an ongoing effort to stimulate novel insights for the dissection of the translational potential of histamine pharmacology. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

Dietary phenylalanine requirements during early and late gestation in healthy pregnant women.

BACKGROUND: Phenylalanine is an indispensable amino acid and, via tyrosine, is the precursor for the neurotransmitters dopamine, norepinephrine, and epinephrine. Currently, dietary requirements for phenylalanine during pregnancy are unknown. OBJECTIVES: This study's aim was to determine phenylalanine requirements (in the presence of excess tyrosine) during early and late gestation using direct amino acid oxidation (DAAO; with l-[1-13C]phenylalanine) and indicator amino acid oxidation (IAAO; with l-[1-13C]leucine). METHODS: Twenty-three healthy women (age: 30.4 ± 3.1 y, mean ± SD) were studied at a range of phenylalanine intakes (5.5-30.5 mg · kg-1 · d-1 in early and late pregnancy using DAAO, and 2.5-30.5 mg · kg-1 · d-1 in late pregnancy using IAAO) for a total of 76 study days. Test intakes were provided as 8 isocaloric and isonitrogenous meals with 1.5 g · kg-1 · d-1 protein and energy at 1.7 times the measured resting energy expenditure. Breath samples were analyzed on an isotope ratio mass spectrometer for 13C enrichment. Phenylalanine requirement was determined using a 2-phase linear regression crossover model to identify a breakpoint in 13CO2 production (representing the mean requirement) in response to phenylalanine intakes. RESULTS: Phenylalanine requirement during early pregnancy was determined to be 15 mg · kg-1 · d-1 (95% CI: 10.4, 19.9 mg · kg-1 · d-1); during late pregnancy, it was determined to be 21 mg · kg-1 · d-1 by DAAO (95% CI: 17.4, 24.7 mg · kg-1 · d-1) and IAAO (95% CI: 10.5, 32.2 mg · kg-1 · d-1). CONCLUSIONS: Our results suggest a higher requirement (40%) for phenylalanine during late pregnancy than during early pregnancy. Moreover, the early pregnancy requirements are higher than the previous adult male requirement (9.1 mg · kg-1 · d-1; 95% CI: 4.6, 13.6 mg · kg-1 · d-1), although the 95% CIs overlap. Both DAAO and IAAO methods provided similar breakpoints in late pregnancy, showing that the DAAO method was appropriate even though low phenylalanine intakes could not be tested. These results have potential implications for gestation stage-specific dietary phenylalanine recommendations in future.This trial was registered at clinicaltrials.gov as NCT02669381.