Oral Iptacopan monotherapy improves outcomes in patients with paroxysmal nocturnal hemoglobinuria: NEJM

France: A recent study has shown improved clinical and hematologic outcomes with iptacopan treatment in anti–C5–treated patients with persistent anemia, in whom iptacopan showed superiority to anti-C5 therapy, and in patients who had not received complement inhibitors.

The study was published online in the New England Journal of Medicine on March 14, 2024.

A lack of oral treatments and persistent hemolytic anemia are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan is a first-in-class oral factor B inhibitor shown to improve hemoglobin levels in these patients.

Against the above background, Régis Peffault de Latour, Université de Paris (R.P.L.), Paris, France, and colleagues assessed iptacopan monotherapy over 24 weeks in patients with hemoglobin levels of less than 10 g per deciliter in two phase 3 trials.

In the first trial, anti–C5–treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan.

In the first trial, the two primary endpoints were a rise in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion. The primary endpoint for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion.

The researchers reported the following findings:

  • In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5–treated patients attained the end-point levels.
  • In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion.
  • In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti–C5–treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion.
  • Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan.

“Iptacopan treatment improved clinical and hematologic outcomes in anti-C5-treated patients with persistent anemia – in whom iptacopan showed superiority to anti-C5 therapy – and in patients who had not received complement inhibitors,” the researchers wrote.

Reference:

Peffault de Latour R, Röth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Wong Lee Lee L, Yap ES, Sicre de Fontbrune F, Marano L, Alashkar F, Gandhi S, Trikha R, Yang C, Liu H, Kelly RJ, Höchsmann B, Kerloeguen C, Banerjee P, Levitch R, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, Risitano AM. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024 Mar 14;390(11):994-1008. doi: 10.1056/NEJMoa2308695. PMID: 38477987.

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High folic acid concentration during early pregnancy risk factor for gestational diabetes: Study

China: A recent retrospective cohort study published in Nutrition has shed light on the association of serum folic acid (FA) levels in response to fasting blood glucose (FBG) in early pregnancy with the risk of gestational diabetes mellitus (GDM).

Hefeng Huang, Shanghai Jiao Tong University, Shanghai, China, and colleagues found that higher serum folic acid levels were significantly correlated with elevated fasting blood glucose concentration in the first trimester and subsequent risk of GDM diagnosed later in pregnancy.

The findings underscore the importance of maintaining an inadequate FA concentration for preserving a reduced risk of gestational diabetes, particularly in women with women with relatively higher blood glucose in early pregnancy. Furthermore, folic acid concentration > 32.5 nmol/L could be a risk factor for GDM.

‘This research indicates that folic acid levels should be monitored during the first trimester from the first prenatal checkup to prevent negative effects of excessive folic acid intake,” the researchers wrote.

There has been an increasing prevalence of folic acid consumption in early pregnancy, concerns have been raised about its potentially negative effect on maternal metabolism. Recent findings on folic acid levels and the first trimester and GDM risk have been inconclusive. Therefore, the research team aimed to examine the association of FA status in early pregnancy with GDM and to examine whether glucose levels can be modulated by folic acid status during the same first trimester.

For this purpose, the researcher performed a retrospective cohort study based on 27,128 Chinese pregnant women who registered during the first prenatal visit from 2015 to 2019. During the 9th to 13th gestational weeks, serum folic acid and FBG concentrations were measured.

Binary logistic regression was applied to estimate odds ratios of GDM by using the serum FA levels quartiles with adjustment for major confounders. To investigate the potential effect of modifying key risk factors for gestational diabetes, the investigators established subgroups, in which analyses were stratified by prepregnancy body mass index (< 18.5, 18.5–23.9, and ≥ 24 kg/m2), age (<25, 25–29, 30–34, and ≥35 y), parity (nulliparous and parous), and family history of diabetes (yes and no).

The study revealed the following findings:

  • A positive association was observed between maternal folate concentrations and fasting blood glucose: the risk for hyperglycemia was higher in those in the middle (Q3) and higher (Q4) quartiles compared with those in Q1 and Q2.
  • A higher risk for gestational diabetes was found in hyperglycemia of early pregnant women with high folate concentrations (Q3: odds ratio = 5.63, and Q4: odds ratio = 5.57) compared with normal fasting glucose mothers with folate concentrations in Q1 and Q2 after accounting for multiple covariables. Similar patterns were observed for different subgroups.
  • Restricted cubic spline plots had a positive correlation of serum folic acid level with fasting blood glucose concentration and the risk of gestational diabetes mellitus in a nonlinear pattern, with 32.5 nmol/L as the cutoff point for folic acid level.

In conclusion, serum FA in early pregnancy is positively linked with early pregnant fasting blood glucose. GDM prevalence is significantly higher in pregnant women with folic acid levels > 32.5 nmol/L compared with < 32.5 nmol/L. For women with FBG ≥ 5.1 mmol/L, FA is significantly positively associated with GDM.

“Therefore, it is suggested that folic acid levels should be monitored during the first trimester from the first prenatal checkup to prevent adverse effects of excessive FA intake,” the researchers wrote.

Reference:

Zhang, C., Liu, Z., Sun, K., Zhao, J., Huang, H., & Zhang, C. (2024). Association of serum folic acid levels in response to fasting blood glucose in early pregnancy with the risk of gestational diabetes mellitus: A retrospective cohort study. Nutrition, 122, 112383. https://doi.org/10.1016/j.nut.2024.112383

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Corticosteroids use reduces proteinuria but fails to delay ESKD in immunoglobulin A nephropathy: Study

Norway: In a cohort of Norwegian patients with immunoglobulin A nephropathy (IgAN), a recent retrospective cohort study showed no impact of corticosteroid therapy on progression to end-stage kidney disease (ESKD), although the therapy reduced proteinuria. Also, the treatment was associated with adverse effects.

“Corticosteroid therapy did not affect the time from diagnosis until end-stage kidney disease among a cohort of patients who all reached end-stage kidney disease,” the researchers wrote in BMC Nephrology.

Multiple agents have been progressing through clinical programs for IgAN treatment, but only budesonide (Tarpeyo) has earned US Food and Drug Administration (FDA) approval thus far. The 2012 Kidney Disease Improving Global Outcomes guideline recommended long-term angiotensin-converting enzyme inhibitor or angiotensin II receptor inhibitor treatment for patients with immunoglobulin A nephropathy and proteinuria > 1 g/d, a threshold that was reduced eventually to 0.5 g/d in the 2021 guideline. However, the efficacy and safety of corticosteroids in this patient population have been debated widely.

Despite several clinical trials, the use of corticosteroid therapy for IgAN treatment remains controversial. While some studies have suggested that corticosteroids are linked with improved clinical outcomes, other studies have questioned the benefits of immunosuppression. Therefore, Thomas Knoop, Department of Medicine, Haukeland University Hospital, Bergen, Norway, and colleagues aimed to describe using corticosteroid therapy combined with supportive therapy in Norwegian patients with IgAN who had progressed to end-stage kidney disease.

For this purpose, they conducted a retrospective cohort study using Norwegian Renal Registry data. One hundred and forty-three patients with primary IgAN who progressed to end-stage kidney disease were categorized into two groups: the corticosteroid group, which had been treated with corticosteroids and supportive therapy, and the non-corticosteroid group, which had undergone only supportive therapy. Of the 143 included patients, 103 underwent supportive therapy alone, and 40 were treated with corticosteroids.

The time to end-stage kidney disease, kidney function, and adverse effects were described. The observation period lasted from the diagnostic kidney biopsy until the initiation of kidney replacement therapy.

The study led to the following findings:

  • Most patients (94%) were treated with renin-angiotensin-system blockade, and all patients reached end-stage kidney disease after a median of 5 years.
  • Time from diagnosis until end-stage kidney disease was similar in the two study groups.
  • During six months of corticosteroid therapy, median eGFR declined from 21 mL/min/1.73 m2 to 20 mL/min/1.73 m2, and median proteinuria decreased from 5.5 g/24 h to 3.0 g/24 h.
  • Most patients (87.5%) treated with corticosteroids reported adverse events.
  • In the linear regression analysis investigating the time to ESKD, age (β = -0.079) and proteinuria at diagnosis (β = -0.50) exhibited statistically significant associations with a delay in the progression to ESKD.

“In this historical cohort of Norwegian patients with advanced and progressive immunoglobulin A nephropathy, corticosteroids decreased proteinuria but did not affect time from diagnosis until end-stage kidney disease among a cohort of patients who all reached ESKD,” the researchers wrote. “Additionally, adverse effects were common in patients treated with corticosteroids.”

Reference:

Rivedal, M., Haaskjold, Y.L., Eikrem, Ø. et al. Use of corticosteroids in Norwegian patients with immunoglobulin a nephropathy progressing to end-stage kidney disease: a retrospective cohort study. BMC Nephrol 25, 42 (2024). https://doi.org/10.1186/s12882-024-03481-6

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Vaginal ring and oral pre-exposure prophylaxis found safe for HIV prevention throughout pregnancy: Study

The monthly dapivirine vaginal ring and daily oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine were each found to be safe for HIV prevention among cisgender women who started using one of them in their second trimester of pregnancy, according to findings presented at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) in Denver. Pregnant people are estimated to be three times more likely to acquire HIV through sexual intercourse than similarly aged people who are not pregnant.

The large clinical study was conducted in South Africa, Uganda and Zimbabwe by the Microbicide Trials Network, an international research network funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health.

The dapivirine ring is made of flexible silicone, continuously releases the antiretroviral drug dapivirine into the vagina, and is replaced monthly by the user. It is approved in several African countries and recommended by the World Health Organization for HIV prevention. Data have been limited on dapivirine ring use in pregnancy. Some participants in previous studies became pregnant while using the ring and discontinued use promptly with no concerning findings, however it had not been specifically studied in this priority population. The safety of oral PrEP with tenofovir disoproxil fumarate and emtricitabine has been well established among pregnant cisgender women with HIV taking them as part of a treatment regimen. Several country regulatory agencies have requested data on oral PrEP use during pregnancy for prevention to complement that evidence.

Participants were aged 18-40 and randomized to receive the ring or oral PrEP until delivery or 41 weeks and six days, whichever came first. Of 248 pregnancies, 1% experienced stillbirth or miscarriage, 95% of deliveries were at term and 4% were preterm. Four percent of live births had congenital anomalies, none of which were related to study products. These trends and other pregnancy complications occurred at a similar frequency to a reference dataset of more than 10,000 deliveries at the same hospitals and no study participants acquired HIV.

According to the authors, the findings, along with those from earlier cohorts in the large clinical study, as well as observed pregnancy outcomes in other studies of these products, demonstrate the ring and oral PrEP to both be safe for HIV prevention throughout pregnancy. 

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80 percent with TB have no persistent cough contrary to prevalent belief: Study

More than 80% of patients with tuberculosis, the world’s most deadly infection, do not have a persistent cough, despite this being seen as a key symptom of the disease. The infection is predominantly transmitted by coughing, but probably also through simply breathing. Research, led by Amsterdam UMC and the Amsterdam Institute for Global Heath and Development, analysed data on more than 600,000 individuals in Africa and Asia and found that 82.8% of those with tuberculosis had no persistent cough and 62.5% had no cough at all. These results are published today inThe Lancet Infectious Diseases.

“Our results indicate the probable reason why, despite huge efforts to diagnose and treat the disease, the tuberculosis (TB) burden across Africa and Asia is hardly declining. We already knew that there was a giant gap between the 10.6 million who get ill with tuberculosis and the 7.5 million cases that were registered by health authorities in 2022,” says Frank Cobelens, Professor of Global Health at Amsterdam UMC and Senior Fellow at the AIGHD.

“A persistent cough is often the entry point for a diagnosis, but if 80% of those with TB don’t have one, then it means that a diagnosis will happen later, possibly after the infection has already been transmitted to many others, or not at all,” he adds.

The study analysed the results of national monitoring schemes in 12 countries, and found that, alongside the lack of a cough, more than a quarter of those with TB had no symptoms at all. With both of these traits being more common in women than in men. Further, the study showed that a quarter of those without cough have high loads of bacteria in their sputum and are probably highly infectious.

“When we take all of these factors into account, it becomes clear that we need to really rethink large aspects of how we identify people with TB. It’s clear that current practice, especially in the most resource-poor settings will miss large numbers of patients with TB. We should instead focus on X-ray screening and the development of new inexpensive and easy-to-use tests” says Cobelens.

Reference:

Logan Stuck, Eveline Klinkenberg, Nahid Abdelgadir Ali, Egbal Ahmed Basheir Abukaraig, Yaw Adusi-Poku, Zeleke Alebachew Wagaw, Prevalence of subclinical pulmonary tuberculosis in adults in community settings: an individual participant data meta-analysis, The Lancet Infectious Diseases, https://doi.org/10.1016/S1473-3099(24)00011-2.

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Laparoscopic hepatectomy as effective as percutaneous radiofrequency ablation for treating small hepatocellular carcinoma: Study

Laparoscopic hepatectomy as effective as percutaneous radiofrequency ablation for treating small hepatocellular carcinoma suggests a study published in the BMC Surgery.

The purpose of this study was to compare the long-term outcomes of laparoscopic hepatectomy (LH) and percutaneous radiofrequency ablation (PRFA) for the treatment of small hepatocellular carcinoma. They systematically searched PubMed, Embase, Web of Science, and Medline from January 2000 to May 2022 for literature comparing the efficacy of LH and PRFA in the treatment of small hepatocellular carcinoma (largest tumour diameter ≤ 3 cm, number of intrahepatic tumours ≤3, or diameter of a single intrahepatic lesion ≤5 cm. They assessed overall survival (OS), recurrence-free survival (RFS), local recurrence and complication rates. Results: A total of 1886 patients with small HCC were included in the 8 studies included in this study, of which 839 underwent LH and 1047 underwent PRAF. The results of the meta-analysis showed that the two groups had the same 3-year (HR: 0.99, 95% CI: 0.67 to 1.47) and 5-year (HR: 1.30, 95% CI: 0.90 to 1.87) OS rates, and the LH group had better 3-year (HR: 0.58, 95% CI: 0.49 to 0.68) and 5-year (HR: 0.56, 95% CI: 0.37 to 0.85) RFS rates. The LH group had a lower local recurrence rate (OR: 0.19, 95% CI: 0.12 to 0.32), but the PRFA group had a lower complication rate. There was no difference in OS between LH and PRFA in the treatment of small HCC. LH had a higher RFS rate and a lower local recurrence rate, but PRFA had a lower complication rate. In general, the long-term efficacy of LH in the treatment of small HCC is better than that of PRFA. Considering the advantages of less trauma and a low complication rate of PRFA, a large number of RCT studies are needed for further verification in the future.

Reference:

Liu, F., Tan, L., Luo, L. et al. Comparison of laparoscopic hepatectomy and percutaneous radiofrequency ablation for the treatment of small hepatocellular carcinoma: a meta-analysis. BMC Surg 24, 83 (2024). https://doi.org/10.1186/s12893-024-02376-5

Keywords:

Laparoscopic hepatectomy, effective, percutaneous, radiofrequency, ablation, treating, small, hepatocellular, carcinoma, Percutaneous radiofrequency ablation, Hepatocellular carcinoma, Meta-analysis, BMC Surgery

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Women involved in car crashes may be more likely to go into shock than men

It is well known that car safety equipment was originally designed with male-representative bodies in mind. This means women sitting in the front row are more likely to suffer severe or fatal injuries in the case of a crash. They are also more likely to be trapped in crashed cars.

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Sleep expert says daylight saving time comes at a cost to your health

Americans set their clocks ahead one hour on Sunday to transition into daylight saving time. That “springing ahead,” however, can come with serious negative health effects—including an increase in total heart attacks and teen sleep deprivation—researchers discovered.

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Infections from nontuberculous mycobacteria are on the rise: New blood test cuts diagnosis time from months to hours

Inhaling nontuberculous mycobacteria is common for most people. The bacteria are found in water systems, soil and dust worldwide and, for many, cause no harm.

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Long COVID ‘indistinguishable’ from other post-viral syndromes a year after infection, researchers find

Long COVID appears to manifest as a post-viral syndrome indistinguishable from seasonal influenza and other respiratory illnesses, with no evidence of increased moderate-to-severe functional limitations a year after infection, according to new research being presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024) in Barcelona, Spain (27-30 April).

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