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BJOG : An International Journal of... Jun 2024An objective and validated index of nausea and vomiting such as the Pregnancy-Unique Quantification of Emesis (PUQE) and HyperEmesis Level Prediction (HELP) tools can be...
An objective and validated index of nausea and vomiting such as the Pregnancy-Unique Quantification of Emesis (PUQE) and HyperEmesis Level Prediction (HELP) tools can be used to classify the severity of NVP and HG. [Grade C] Ketonuria is not an indicator of dehydration and should not be used to assess severity. [Grade A] There are safety and efficacy data for first line antiemetics such as anti (H1) histamines, phenothiazines and doxylamine/pyridoxine (Xonvea®) and they should be prescribed initially when required for NVP and HG (Appendix III). [Grade A] There is evidence that ondansetron is safe and effective. Its use as a second line antiemetic should not be discouraged if first line antiemetics are ineffective. Women can be reassured regarding a very small increase in the absolute risk of orofacial clefting with ondansetron use in the first trimester, which should be balanced with the risks of poorly managed HG. [Grade B] Metoclopramide is safe and effective and can be used alone or in combination with other antiemetics. [Grade B] Because of the risk of extrapyramidal effects metoclopramide should be used as second-line therapy. Intravenous doses should be administered by slow bolus injection over at least 3 minutes to help minimise these. [Grade C] Women should be asked about previous adverse reactions to antiemetic therapies. If adverse reactions occur, there should be prompt cessation of the medications. [GPP] Normal saline (0.9% NaCl) with additional potassium chloride in each bag, with administration guided by daily monitoring of electrolytes, is the most appropriate intravenous hydration. [Grade C] Combinations of different drugs should be used in women who do not respond to a single antiemetic. Suggested antiemetics for UK use are given in Appendix III. [GPP] Thiamine supplementation (either oral 100 mg tds or intravenous as part of vitamin B complex (Pabrinex®)) should be given to all women admitted with vomiting, or severely reduced dietary intake, especially before administration of dextrose or parenteral nutrition. [Grade D] All therapeutic measures should have been tried before considering termination of pregnancy. [Grade C].
Topics: Humans; Female; Pregnancy; Hyperemesis Gravidarum; Antiemetics; Ondansetron; Morning Sickness; Nausea; Pyridoxine; Metoclopramide; Severity of Illness Index; Pregnancy Complications
PubMed: 38311315
DOI: 10.1111/1471-0528.17739 -
Nature Communications Apr 2024The analysis of neural circuits has been revolutionized by optogenetic methods. Light-gated chloride-conducting anion channelrhodopsins (ACRs)-recently emerged as...
The analysis of neural circuits has been revolutionized by optogenetic methods. Light-gated chloride-conducting anion channelrhodopsins (ACRs)-recently emerged as powerful neuron inhibitors. For cells or sub-neuronal compartments with high intracellular chloride concentrations, however, a chloride conductance can have instead an activating effect. The recently discovered light-gated, potassium-conducting, kalium channelrhodopsins (KCRs) might serve as an alternative in these situations, with potentially broad application. As yet, KCRs have not been shown to confer potent inhibitory effects in small genetically tractable animals. Here, we evaluated the utility of KCRs to suppress behavior and inhibit neural activity in Drosophila, Caenorhabditis elegans, and zebrafish. In direct comparisons with ACR1, a KCR1 variant with enhanced plasma-membrane trafficking displayed comparable potency, but with improved properties that include reduced toxicity and superior efficacy in putative high-chloride cells. This comparative analysis of behavioral inhibition between chloride- and potassium-selective silencing tools establishes KCRs as next-generation optogenetic inhibitors for in vivo circuit analysis in behaving animals.
Topics: Animals; Caenorhabditis elegans; Neurons; Optogenetics; Zebrafish; Channelrhodopsins; Humans; Drosophila; Potassium Channels; Chlorides; Animals, Genetically Modified; Behavior, Animal; HEK293 Cells; Drosophila melanogaster
PubMed: 38658537
DOI: 10.1038/s41467-024-47203-w -
Circulation Jul 2023Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As prespecified secondary end points, the TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF.
METHODS
TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomly assigned in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on prespecified secondary end points, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; assessed as adjusted mean difference in change from baseline; range, 0-100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (range, 0-6; score ≥3 supporting evaluation for depression) over 12 months.
RESULTS
Baseline data were available for 2787 (97.5%) patients for KCCQ-CSS and 2624 (91.8%) patients for Patient Health Questionnaire-2. Median (interquartile range) baseline KCCQ-CSS was 42 (27-60) in the torsemide group and 40 (24-59) in the furosemide group. At 12 months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference, 0.06 [95% CI, -2.26 to 2.37]; =0.96) or the proportion of patients with Patient Health Questionnaire-2 score ≥3 (15.1% versus 13.2%: =0.34). Results for KCCQ-CSS were similar at 1 month (adjusted mean difference, 1.36 [95% CI, -0.64 to 3.36]; =0.18) and 6-month follow-up (adjusted mean difference, -0.37 [95% CI, -2.52 to 1.78]; =0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent before hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization.
CONCLUSIONS
Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, previous loop diuretic use, and baseline health status.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT03296813.
Topics: Humans; Furosemide; Torsemide; Sodium Potassium Chloride Symporter Inhibitors; Quality of Life; Heart Failure; Stroke Volume
PubMed: 37212600
DOI: 10.1161/CIRCULATIONAHA.123.064842 -
Brain : a Journal of Neurology Dec 2023Disinhibition during early stages of Alzheimer's disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the...
Disinhibition during early stages of Alzheimer's disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer's disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex. KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-β 42 (Aβ42). Acute administration of Aβ42 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer's disease-related cognitive decline. These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer's disease-related cognitive decline; they confirm target engagement, where the therapeutic intervention takes place, and its effectiveness.
Topics: Mice; Animals; Alzheimer Disease; Chlorides; Amyloid beta-Peptides; Cognitive Dysfunction; Symporters; Mutation; Disease Models, Animal
PubMed: 37551444
DOI: 10.1093/brain/awad250 -
The Journal of Clinical Investigation Nov 2023Consumption of low dietary potassium, common with ultraprocessed foods, activates the thiazide-sensitive sodium chloride cotransporter (NCC) via the with no (K) lysine...
Consumption of low dietary potassium, common with ultraprocessed foods, activates the thiazide-sensitive sodium chloride cotransporter (NCC) via the with no (K) lysine kinase/STE20/SPS1-related proline-alanine-rich protein kinase (WNK/SPAK) pathway to induce salt retention and elevate blood pressure (BP). However, it remains unclear how high-potassium "DASH-like" diets (dietary approaches to stop hypertension) inactivate the cotransporter and whether this decreases BP. A transcriptomics screen identified Ppp1Ca, encoding PP1A, as a potassium-upregulated gene, and its negative regulator Ppp1r1a, as a potassium-suppressed gene in the kidney. PP1A directly binds to and dephosphorylates NCC when extracellular potassium is elevated. Using mice genetically engineered to constitutively activate the NCC-regulatory kinase SPAK and thereby eliminate the effects of the WNK/SPAK kinase cascade, we confirmed that PP1A dephosphorylated NCC directly in a potassium-regulated manner. Prior adaptation to a high-potassium diet was required to maximally dephosphorylate NCC and lower BP in constitutively active SPAK mice, and this was associated with potassium-dependent suppression of Ppp1r1a and dephosphorylation of its cognate protein, inhibitory subunit 1 (I1). In conclusion, potassium-dependent activation of PP1A and inhibition of I1 drove NCC dephosphorylation, providing a mechanism to explain how high dietary K+ lowers BP. Shifting signaling of PP1A in favor of activation of WNK/SPAK may provide an improved therapeutic approach for treating salt-sensitive hypertension.
Topics: Animals; Mice; Blood Pressure; Solute Carrier Family 12, Member 3; Protein Serine-Threonine Kinases; Sodium Chloride; Potassium, Dietary; Kidney; Hypertension; Potassium; Phosphorylation
PubMed: 37676724
DOI: 10.1172/JCI158498 -
BMJ Case Reports Sep 2023An ectopic pregnancy (EP) accounts for 1-2% of all pregnancies, of which 90% implant in the fallopian tube. An abdominal ectopic pregnancy (AEP) is defined as an ectopic...
An ectopic pregnancy (EP) accounts for 1-2% of all pregnancies, of which 90% implant in the fallopian tube. An abdominal ectopic pregnancy (AEP) is defined as an ectopic pregnancy occurring when the gestational sac is implanted in the peritoneal cavity outside the uterine cavity or the fallopian tube. Implantation sites may include the omentum, peritoneum of the pelvic and abdominal cavity, the uterine surface and abdominal organs such as the spleen, intestine, liver and blood vessels. Primary abdominal pregnancy results from fertilisation of the ovum in the abdominal cavity and secondary occurs from an aborted or ruptured tubal pregnancy. It represents a very rare form of an EP, occurring in <1% of cases. At early gestations, it can be challenging to render the diagnosis, and it can be misdiagnosed as a tubal ectopic pregnancy. An AEP diagnosed >20 weeks' gestation, caused by the implantation of an abnormal placenta, is an important cause of maternal-fetal mortality due to the high risk of a major obstetric haemorrhage and coagulopathy following partial or total placental separation. Management options include surgical therapy (laparoscopy±laparotomy), medical therapy with intramuscular or intralesional methotrexate and/or intracardiac potassium chloride or a combination of medical and surgical management. The authors present the case of a multiparous woman in her early 30s presenting with heavy vaginal bleeding and abdominal pain at 8 weeks' gestation. Her beta-human chorionic gonadotropin (bHCG) was 5760 IU/L (range: 0-5), consistent with a viable pregnancy. Her transvaginal ultrasound scan suggested an ectopic pregnancy. Laparoscopy confirmed an AEP involving the pelvic lateral sidewall. Her postoperative 48-hour bHCG was 374 IU/L. Due to the rarity of this presentation, a high index of clinical suspicion correlated with the woman's symptoms; bHCG and ultrasound scan is required to establish the diagnosis to prevent morbidity and mortality.
Topics: Pregnancy; Female; Humans; Pregnancy, Abdominal; Placenta; Chorionic Gonadotropin, beta Subunit, Human; Pregnancy, Tubal; Methotrexate
PubMed: 37775278
DOI: 10.1136/bcr-2022-252960 -
The Journal of Clinical Endocrinology... Aug 2023Differential diagnosis of thiazide-associated hyponatremia (TAH) is challenging. Patients can either have volume depletion or a syndrome of inappropriate antidiuresis...
CONTEXT
Differential diagnosis of thiazide-associated hyponatremia (TAH) is challenging. Patients can either have volume depletion or a syndrome of inappropriate antidiuresis (SIAD)-like presentation.
OBJECTIVE
To evaluate the impact of the simplified apparent strong ion difference in serum (aSID; sodium + potassium - chloride) as well as the urine chloride and potassium score (ChU; chloride - potassium in urine) in the differential diagnosis of TAH, in addition to assessment of fractional uric acid excretion (FUA).
METHODS
Post hoc analysis of prospectively collected data from June 2011 to August 2013 from 98 hospitalized patients with TAH < 125 mmol/L enrolled at University Hospital Basel and University Medical Clinic Aarau, Switzerland. Patients were categorized according to treatment response in volume-depleted TAH requiring volume substitution or SIAD-like TAH requiring fluid restriction. We computed sensitivity analyses with ROC curves for positive predictive value (PPV) and negative predictive value (NPV) of aSID, ChU, and FUA in differential diagnosis of TAH.
RESULTS
An aSID > 42 mmol/L had a PPV of 79.1% in identifying patients with volume-depleted TAH, whereas a value < 39 mmol/L excluded it with a NPV of 76.5%. In patients for whom aSID was inconclusive, a ChU < 15 mmol/L had a PPV of 100% and a NPV of 83.3%, whereas FUA < 12% had a PPV of 85.7% and a NPV of 64.3% in identifying patients with volume-depleted TAH.
CONCLUSION
In patients with TAH, assessment of aSID, potassium, and chloride in urine can help identifying patients with volume-depleted TAH requiring fluid substitution vs patients with SIAD-like TAH requiring fluid restriction.
Topics: Humans; Hyponatremia; Chlorides; Thiazides; Inappropriate ADH Syndrome; Potassium; Diagnosis, Differential; Sodium Chloride
PubMed: 36899489
DOI: 10.1210/clinem/dgad133 -
Heart Rhythm Aug 2023
Topics: Humans; Arrhythmias, Cardiac; Long QT Syndrome; Electrocardiography
PubMed: 37517862
DOI: 10.1016/j.hrthm.2023.02.026 -
Perfusion Nov 2023A basic prerequisite for a good surgical outcome in heart surgery is optimal myocardial protection. However, cardioplegia strategies used in adult cardiac surgery are...
INTRODUCTION
A basic prerequisite for a good surgical outcome in heart surgery is optimal myocardial protection. However, cardioplegia strategies used in adult cardiac surgery are not directly transferable to infant hearts. Paediatric microplegia, analogous to Calafiore cardioplegia used in adult cardiac surgery, offers the advantage of safe myocardial protection without haemodilution. The use of concentration-dependent paediatric microplegia is new in clinical implementation.
MATERIAL AND METHODS
Paediatric microplegia has been in clinical use in our institution since late 2014. It is applied via an 1/8 inch tube of a S5-HLM roller pump (LivaNova, Italy). As cardioplegic additive, a mixture of potassium (K) 20 mL (2 mmol/mL potassium chloride 14.9% Braun) and magnesium (Mg) 10 mL (4 mmol/mL Mg-sulphate Verla® i. v. 50%) is fixed into a syringe-pump (B. Braun, Germany). This additive is mixed with arterial patient blood from the oxygenator in different flowdependent ratios to form an effective cardioplegia.
TECHNIQUE
After microplegia application of initially 25 mmol/L K with 11 mmol/L Mg for 2 min, a safe cardioplegic cardiac arrest is achieved, which after release of the coronary circulation, immediately returns to a spontaneous cardiac-rhythm. In the case of prolonged aortic clamping, microplegia is repeated every 20 min with a reduction of the application dose of K by 20% and Mg by 30% (20 mmol/L K; 8.5 mmol/L Mg) and a further reduction down to a maintenance dose (15 mmol/L K; 6 mmol/L Mg) after additional 20 min.
SUMMARY
The microplegia adapted to the needs of paediatric myocardium is convincing due to its simple technical implementation for the perfusionist while avoiding haemodilution. However, the required intraoperative interval of microplegia of approx. 20 min demands adapted intraoperative management from the surgeon.
Topics: Adult; Humans; Child; Heart Arrest, Induced; Cardiac Surgical Procedures; Myocardium; Italy; Cardioplegic Solutions
PubMed: 36121780
DOI: 10.1177/02676591221127926