Takeda bags accelerated USFDA nod for Iclusig with chemotherapy in adult patients with newly diagnosed Ph+ ALL

Osaka: Takeda has announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for ICLUSIG (ponatinib) for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.

This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. This accelerated approval application was granted Priority Review and evaluated under the Real-Time Oncology Review (RTOR) program, an FDA initiative designed to expedite the delivery of cancer medicines by allowing components of an application to be reviewed before submission of the complete application.

“This label expansion for ICLUSIG is an incredibly exciting milestone, allowing U.S. adult patients with newly diagnosed Ph+ ALL to have an approved, targeted treatment option in the frontline,” said Awny Farajallah, MD, chief medical officer, oncology at Takeda. “We are thrilled that the FDA has recognized the potential of ICLUSIG to fill a large gap in care for these patients and look forward to seeing the impact this can have on people with this rare and aggressive form of cancer.”

The approval was supported by data from the PhALLCON study – the first, global, Phase 3, registrational, head-to-head clinical trial in adults with newly diagnosed Ph+ ALL. The study, in which patients received either ICLUSIG or imatinib plus reduced-intensity chemotherapy, met its primary endpoint of MRD negative CR at the end of induction. MRD-negative CR is a composite endpoint defined in alignment with the FDA that reflects deep molecular and clinical responses and is an important prognostic indicator for long-term outcomes for patients with Ph+ ALL. ICLUSIG demonstrated superiority compared to imatinib, with patients who received ICLUSIG achieving a greater than two-fold improvement in the rate of MRD-negative CR at the end of induction (cycle 3). In the trial, the safety profile of ICLUSIG was comparable to imatinib, and no new safety signals were identified.

“Ph+ ALL is an extremely aggressive cancer and patients with this disease suffer from poor outcomes. There has long been a need for a potent TKI that can suppress mutation development and elicit deep responses in the frontline,” said Elias Jabbour, MD, The University of Texas MD Anderson Cancer Center and lead investigator of the PhALLCON trial. “Ponatinib may help address these factors and impact long-term outcomes.”

ICLUSIG is a kinase inhibitor indicated in the U.S. for adult patients with newly diagnosed Ph+ ALL in combination with chemotherapy. This indication is approved under accelerated approval based on MRD-negative CR at the end of induction. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). In addition, it is approved as monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL, chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated or T315I-positive CML (chronic phase, accelerated phase, or blast phase). ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

Ph+ ALL is a rare form of ALL that affects approximately 25% of adult ALL patients in the U.S. and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome. In patients who are Philadelphia chromosome-positive (Ph+), an abnormal chromosome is formed when pieces of chromosomes 9 and 22 switch with each other. This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR::ABL1 and is associated with Ph+ ALL.

Read also: Biological E, Takeda join hands to accelerate access to Dengue Vaccine in endemic areas

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Replacing sugar with sweeteners can improve weight loss control over the long term in overweight adults

New research being presented at this year’s European Congress on Obesity (ECO) in Venice, Italy (12-15 May), suggests that replacing sugar-sweetened food and drinks with low/no energy sweetened products can help weight control for at least one year after rapid weight loss in adults, without increasing the risk of type 2 diabetes or cardiovascular disease.

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Ahmedabad doctor cheated of Rs 6 crore in real estate fraud

Ahmedabad: In a distressing turn of events, a 50-year-old doctor residing in Thaltej has reportedly fallen victim to an alleged scam by a realtor, promising lucrative returns on a realty venture in Gurukul dating back to 2018.   

The complainant runs a hospital near Sattadhar crossroads and he has lodged a First Information Report (FIR) with the Detection of Crime Branch (DCB) police, identifying a fellow resident of Thaltej as the primary accused in the case.
Also Read:KEM doctor swindled out of Rs 7.33 lakh by cyber fraudsters

According to the details mentioned in the FIR, the accused purportedly enticed him with the promise of a Rs 50 lakh return after five years, coupled with the allocation of three commercial shops within the scheme. Allegedly, the victim trusted the accused with a substantial sum amounting to Rs 6.25 crore. The victim exhausted his personal savings and also took loans procured from acquaintances, reports the Times of India.  
He stated that the culprit provided him with allotment documents for the three shops in 2019. However, in 2023, to his utter disbelief, he came to know that the shops he believed to be rightfully his had been sold to different individuals. Adding to the distress, he only received a paltry sum of Rs 48 lakh as a return on his significant investment. Upon confronting the culprit regarding the discrepancy, the realtor responded with threats of dire repercussions. Moreover, he alleged that the accused obtained funds from him and his business partners without their prior knowledge or their consent. 
Also Read:GMC Bhadradi Kothagudem female medicos allegedly being mistreated by Principal: TJUDA demands investigation

In response to his grievance, the DCB police have registered a case against the accused, charging him with breach of trust and cheating under the Indian Penal Code (IPC). Subsequently, an investigation into the matter has been initiated to ascertain the veracity of the allegations and bring the perpetrator to justice.

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Cefuroxime in Lower Respiratory Infections: Clinical Review

Unmasking the Global Challenge of Lower Respiratory Tract Infections:

Lower respiratory tract infections (LRTIs) are a major public health concern, causing considerable illness and death in all age groups. (1). The World Health Organization identified LRTIs as the fourth leading cause of death in communicable diseases (2) and the second leading cause of disability globally, causing approximately 2.74 million deaths annually (3).

In India, LRTIs contribute significantly to disease burdens, with a 7-fold disparity in disability-adjusted life years (DALY) rate (4). Few studies reported the rates of clinically defined LRTIs and hospitalizations associated with LRTIs to be 248.3 and 12.7 per 1000 person-years, respectively in India (5).

Navigating the Spectrum of Lower Respiratory Tract Infections:

The European Respiratory Society (ERS) along with The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) defined LRTIs as “An acute illness (present for 21 days or less), usually with cough as the main symptom, with at least one other lower respiratory tract symptom (sputum production, dyspnea, wheeze or chest discomfort/pain) and no alternative explanation (e.g. sinusitis or asthma) (6).” LRTIs is a broader term comprising acute bronchitis, pneumonia, and exacerbations of chronic lung disease and there is a huge overlap of clinical presentations of various infections of LRT. Indian statistics revealed that advanced age, being male, having chronic bronchitis, experiencing co-morbidities, smoking, belonging to the lower quintile of wealth, and using solid fuel in the household were some of the identified risk factors for LRTIs (5).

Management of LRTI: Overview

Antibiotics are specifically advised for chronic obstructive pulmonary disease (COPD) exacerbations with increased dyspnea, sputum volume, and purulence. The empirical use of antiviral treatment for suspected influenza is generally discouraged. In primary care setting, cough suppressants, expectorants, mucolytics, antihistamines, inhaled corticosteroids, and bronchodilators are refrained for acute LRTI. Antibiotic treatment is recommended for confirmed or suspected pneumonia, and consideration should be given to patients with LRTI and serious co-morbidities such as exacerbations of COPD, cardiac failure, insulin-dependent diabetes, or neurological disorders (6).

Examining the Significance of Cefuroxime in LRTIs (7):

Healthcare providers administer a range of antibiotics to address LRTIs, with Cefuroxime, a second-generation cephalosporin, standing out. It undergoes rapid hydrolysis, forming the active parent compound, rendering it a noteworthy option.

  • Cefuroxime exhibits a wide range of antibacterial activity in vitro, encompassing methicillin-sensitive staphylococci (MRSA) and other common respiratory pathogens like Streptococcus pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis and group A β-hemolytic streptococci. It also has broad-spectrum activity against the β -lactamase-positive respiratory pathogens H. influenzae and M. catarrhalis; and is also active against penicillin-susceptible and -intermediate strains of S. pneumonia.
  • The Clinical and Laboratory Standards Institute (CLSI) has put forth various breakpoints for cefuroxime as follows (7):

MIC Breakpoints

S. pneumonia

≤0.5 mg/L

Susceptible

1mg/L

Intermediate susceptibility

≥2mg/L

resistant

Haemophilus influenzae and H. parainfluenza

≤ 4

Susceptible

8

Intermediate susceptibility

≥ 16

resistant

The comparative MIC90 values, kill time kinetics, Cmax & Tmax have been elaborated as follows (8):

a. MIC90 values compared to other antibiotics:

Pathogen

Cefuroxime

Cefaclor

Amox-Clav

Streptococcus pneumoniae Penicillin Susceptible

<0.012

1

≤0.06

Streptococcus pyogenes

≤0.25

≤1

NA

Β-lactamase positive Haemophilus influenza

1-2

32-64

2-4

This indicates a better in-vitro antibacterial activity of cefuroxime against various pathogens compared to cefaclor and amoxicillin/clavulanic acid.

b. Kill Time Kinetics (7)

S.aureus & H.influenza

Faster lysis (onset of lysis- 1 hr)

MIC – 0.5 mg/L

P. mirabilis, and E. coli

Slower lysis (onset of lysis- 1to 5 hrs)

MIC – 2.0 and 4.0 mg/L, respectively

In the context of the clinical setting, these results suggest that cefuroxime prevents the dissemination of S Aureus and H. influenza in the bloodstream.

c. Cmax and tmax of cefuroxime at different concentrations (7):

Dosage

Cmax (mg/L)

Tmax (h)

Single dose 125mg

2.1

2.2

Single dose 250mg

4.1-4.8

2.1-2.5

Single dose 500mg

4.4-7.9

2.4-3.0

Single dose 100mg

13.6

2.2

Multiple doses 250 mg every 12 h

4.01

2.77

LRTIs 500mg every 12h for 5 days

9.1

2.75

The pharmacokinetic profile of cefuroxime (administered immediately after a meal) is linear over the 125 to 1000mg dose range.

d. Clinical Response Rates: For treating LRTIs like acute bronchitis, acute exacerbations of chronic bronchitis, or community-acquired pneumonia, cefuroxime (given at 250 or 500mg twice daily for 5 to 10 days) exhibited efficacy, achieving clinical responses (cure or improvement) in over 72% of patients (7).

  • The U.S. Food and Drug Administration has put forth the dosage recommendations of Cefuroxime Axetil tablet for various infections (10)

Adults and Adolescents (13years and older)

Dosage

Acute bacterial exacerbations of chronic bronchitis (mild to moderate)

250 or 500 mg PO every 12 hours for 10 days

Secondary bacterial infections of acute bronchitis

250 or 500 mg PO every 12 hours for 5-10 days

Comprehensive Review of Literature on Clinical Efficacy of Cefuroxime:

  • Cefuroxime in Lower Respiratory Infections: In a multinational, non-blinded trial involving 512 hospitalized patients with LRTIs, the clinical and bacteriological effectiveness of intravenous cefuroxime (750 mg thrice a day) followed by oral cefuroxime (500 mg twice a day) was compared to intravenous amox-clav (1.2g thrice a day) followed by oral amox-clav (625 mg thrice a day). After 48 to 72 hours of parenteral therapy, both groups having 256 patients each, underwent five days of oral treatment. The results showed 87.1% and 72.8% in the cefuroxime group, and 85.9% and 70% in the amoxiclav group achieved clinical improvement and bacterial clearance, respectively. This suggests that the “follow-on” therapy with Cefuroxime/cefuroxime axetil is as clinically and bacteriologically effective as amox-clav, with the added convenience of twice-daily oral administration (11).
  • Cefuroxime – Efficacious and Safe: A multicenter, randomized clinical trial compared the clinical and bacteriologic efficacies and the safety of cefuroxime axetil with amoxicillin-clavulanate in treating secondary bacterial infections of acute bronchitis. The study enrolled 537 patients who received either 5 days or 10 days of cefuroxime axetil (250 mg twice daily) or 10 days of treatment with amoxicillin-clavulanate at 500 mg three times daily. Upon evaluation of clinical outcome, cure (complete resolution of clinical signs and symptoms of infection at the 1- to 3-day and 13- to 15-day posttreatment visits), or improvement (clinical signs and symptoms substantially reduced but not entirely resolved),) treatment with cefuroxime axetil for 5 days achieved 82%, cefuroxime axetil for 10 days gained 86%, and 83% with amoxicillin-clavulanate, respectively. A higher incidence of drug-related adverse events was observed with amoxicillin-clavulanate treatment (P=0.001). These results indicate that treatment with cefuroxime axetil is effective and safe in patients with acute bronchitis. (12)
  • Cefuroxime in Treatment of Severe LRTIs: In a double-blind, randomised trial, cefuroxime and ampicillin were assessed for treating severe LRTIs. Cefuroxime, administered at 750 mg to 57 patients, and ampicillin, at 500 mg to 54 patients, were delivered via intramuscular injection thrice daily for 7-10 days. The study population exhibited acute exacerbations of chronic bronchitis with or without pneumonia, with a subset presenting bronchiectasis and nearly a quarter having an underlying bronchial carcinoma. By the end of the treatment, sputum, which was initially consistently mucopurulent, transitioned to mucoid in 87.7% of cefuroxime-treated patients versus 48.1% of ampicillin-treated patients, and a satisfactory clinical response was noted in 94.7% and 68.5%, respectively, with both differences proving statistically significant. Thus, the study showed that cefuroxime was more efficacious than ampicillin for LRTIs (13).
  • The bacterial eradication and clinical efficacy of cefuroxime compared to other antibiotics have been represented in a tabular form as given below (7,8)

Study design

Infection

Cefuroxime (n){dose}

Comparator (n){dose}

Clinical response rate (complete resolution) *cefuroxime/comparator

Bacteriological response rate (complete resolution) *cefuroxime/comparator

Multicentre, non-blind

Acute bronchitis and acute exacerbations of chronic bronchitis

Cefuroxime (98) {250 mg twice a day}

cefprozil (97) {250mg twice a day}

94/91

82/79

Multicenter

Community-acquired pneumonia

Cefuroxime (69){10mg/kg mg twice a day}

Ceftibuten{10mg/kg twice a day}

93/80

32 /36

*Expressed in % of patients

Cefuroxime continues to hold an important place in the management of community infections in Indian real-life setting: The Indian review revisiting scientific evidences on the efficacy and safety of Cefuroxime axetil concluded that cefuroxime can be a proper empiric choice antibiotic for Indian physicians treating respiratory tract infections, urinary tract infections, and skin and soft tissue infections in their outpatient departments. Also, in an era of rapidly increasing bacterial resistance, empirical treatment with cefuroxime axetil may ensure the proper use of newer antibacterial medications, minimising bacterial resistance. (14,15)

Consideration of Cefuroxime: Glance at Guidelines

  • The Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines for Adult Community-Acquired Pneumonia Management endorse cefuroxime (500 mg twice daily) for outpatient treatment in individuals with comorbidities, including chronic heart, lung, liver, or renal diseases; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressive conditions or drug use; and recent antimicrobial use within the past 3 months (16).
  • Cefuroxime is endorsed by the Indian Council of Medical Research (ICMR) for outpatient treatment for adult community-acquired pneumonia (CAP), both for individuals without comorbidities and those with comorbidities or recent antibiotic use within three months. The recommended dosage of Cefuroxime is 500 mg twice daily orally or 1.5 gm twice daily IV in adults. (17)

Take Home Messages

  • LRTIs are a substantial health concern in India, carrying a significant 7-fold difference in DALY rate with clinically defined LRTI and associated hospitalization rates at 248.3 and 12.7 per 1000 person-years, respectively.
  • LRTIs include acute bronchitis, pneumonia, and exacerbations of chronic lung diseases like COPD and Acute Exacerbation of Chronic Bronchitis, with antibiotics playing a major role in their management.
  • Cefuroxime is a second-generation cephalosporin with a wide antibacterial spectrum and is a safe, clinically and bacteriologically effective antibiotic.
  • Cefuroxime (500 mg twice daily) is recommended by both the Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines and the Indian Council of Medical Research (ICMR) for outpatient treatment of adult community-acquired pneumonia.
  • Cefuroxime axetil could be considered a suitable empirical treatment for various community-acquired infections, particularly those caused by beta-lactamase-producing strains of common respiratory pathogens.
  • In a time marked by swiftly evolving bacterial resistance, initiating empirical therapy with antibacterial agents like cefuroxime axetil may help in averting the development of resistance to newer antibacterial agents. This approach aims to ensure the judicious use of these advanced drugs and potentially forestall the emergence of bacterial resistance to them.

References:

1. GBD 2015 LRI Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Infect Dis. 2017;17(11):1133-1161. doi:10.1016/S1473-3099(17)30396-1

2. A visualized overview of global and regional trends in the leading causes of death and disability 2000-2019. www.who.int. https://www.who.int/data/stories/leading-causes-of-death-and-disability-2000-2019-a-visual-summary

3. Feldman C, Shaddock E. Epidemiology of lower respiratory tract infections in adults. Expert Rev Respir Med. 2019;13(1):63-77. doi:10.1080/17476348.2019.1555040

4. Council I, India, Washington. O. India: Health of the Nation’s States: The India State-Level Disease Burden Initiative: Disease Burden Trends in the States of India, 1990 to 2016. Indian Council Of Medical Research; 2017

5. Kumar R, Dar L, Amarchand R, et al. Incidence, risk factors, and viral etiology of community-acquired acute lower respiratory tract infection among older adults in rural north India. J Glob Health. 2021;11:04027. Published 2021 Apr 3. doi:10.7189/jogh.11.04027

6. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections–full version. Clin Microbiol Infect. 2011;17 Suppl 6(Suppl 6):E1-E59. doi:10.1111/j.1469-0691.2011.03672.x

7. Perry CM, Brogden RN. Cefuroxime axetil. A review of its antibacterial activity, pharmacokinetic properties, and therapeutic efficacy. Drugs. 1996;52(1):125-158. doi:10.2165/00003495-199652010-00009.

8. Scott LJ, Ormrod D, Goa KL. Cefuroxime axetil: an updated review of its use in the management of bacterial infections. Drugs. 2001;61(10):1455-1500. doi:10.2165/00003495-200161100-00008.

9. Gautam Y. A review: antimicrobial activity of cefuroxime axetil. W. Jour. Pharm. Res. 2023;12(11):579-588. Doi:10.20959/wjpr202311-28847.

10. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/050605s048,050672s034lbl.pdf

11. Brambilla, C., Kastanakis, S., Knight, S. et al. Cefuroxime and cefuroxime axetil versus amoxicillin plus clavulanic acid in the treatment of lower respiratory tract infections. Eur. J. Clin. Microbiol. Infect. Dis. 11, 118–124 (1992). https://doi.org/10.1007/BF01967062.

12. Henry D, Ruoff GE, Rhudy J, Puopolo A, Drehobl M, Schoenberger J, Giguere G, Collins JJ. Effectiveness of short-course therapy (5 days) with cefuroxime axetil in treatment of secondary bacterial infections of acute bronchitis. Antimicrob Agents Chemother. 1995 Nov;39(11):2528-34. doi: 10.1128/AAC.39.11.2528.

13. Pines A, Raafat H, Khorasani M, Mullinger BM. Cefuroxime and ampicillin were compared in a double-blind study in the treatment of lower respiratory tract infections. Chemotherapy. 1981;27(6):459-465. doi:10.1159/000238016.

14. Badhwar VR, Ganapathy S, Prabhudesai PP, Tulara NK, Varaiya AY, Vyas D. A Relook of Cefuroxime in Community Infections: An Option Still Beneficial. J Assoc Physicians India. 2016 Jul;64(7):95-101.

15. Kumar S, Jeet K, Devi A, Kumar P, Kumar N. A Short Review on Cefueoxime Axetil Tablet. Asian J Pharm Res Dev [Internet]. 2022 Aug. 14 [cited 2024 Feb. 14];10(4):pdf. Available from: https://www.ajprd.com/index.php/journal/article/view/1148

16. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2(Suppl 2): S27-S72. doi:10.1086/511159

17. Indian Council on Medical Research. Treatment Guidelines for Antimicrobial Use in Common Syndrome 2022. Accessed on 22nd January 2024 from https://main.icmr.nic.in/content/guidelines-0 or https://play.google.com/store/apps/details?id=com.icmr.amr_treatment_guidelines&hl=en&gl=US

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Postpone Exams By 2 Months! 2nd year BDS Students Urge MP Medical Science University

Indore: The second-year Bachelor of Dental Surgery (BDS) students have appealed to the Madhya Pradesh Medical Science University (MPMSU), Jabalpur, for a two-month extension in the examination schedule.

Voicing their grievances, the students have forwarded a memorandum to the Dean of MGM Medical College, pressing for a revision in the examination timetable. They asserted that insufficient time for semester preparation and incomplete mandatory teaching, spanning 240 days, have left them ill-prepared for the impending exams.
Also Read:MP: Devi Ahilya Hospital running sans permission sealed

MPMSU has issued the schedule for medical exams and the BDS second-year exams are supposed to take place on April 3. The students have pointed out that it has been only a few months since completing the previous semester’s exam. Hence, they did not have the time to prepare for the third semester. Moreover, the students are under tremendous pressure considering that the syllabus and preclinical quota have not been completed.
Some of the BDS students told Free Press Journal, “We have appealed to the Dean of MGM Medical College, as the college is the regional center of MPMSU. We have also dashed off letters to the vice-chancellor, registrar, and exam controller of the university for the same.” 
“About 120 students of Government Dental College and Indore Dental College, Rau, are being affected by the early exams,” they added.
Taking cognizance of the demands of the students, Dean Dr. Sanjay Dixit stated that the authorities will forward the demands of the students to MPMSU. The authorities will discuss the matter and make a decision regarding the postponement of the examination. 
Also Read:Only gynaecologists can examine sexual assault survivors: Kerala HC order

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Long term Profile attractiveness similar in extraction and nonextraction groups among patients with class I and II malocclusion: Study

Long term Profile attractiveness similar in extraction and nonextraction groups among patients with class I and II malocclusion suggests a study published in the American Journal of Orthodontics and Dentofacial Orthopedics.

The objective of this study was to compare the profile attractiveness in subjects treated with and without extractions after the long-term 35-year follow-up, according to laypeople, dentists, and orthodontists. A total of 40 patients with Class I and II malocclusion were divided into 2 groups, according to the treatment protocol: extraction (E) group, extractions of 4 premolars (n = 24), with mean pretreatment (T1), posttreatment (T2), and long-term posttreatment (T3) ages of 13.13, 15.50 and 49.56 years, respectively. The mean treatment time (T2 – T1) was 2.37 years, and the long-term follow-up (T3 – T2) was 34.19. Nonextraction (NE) group (n = 16), with mean ages at T1, T2, and T3 of 13.21, 15.07, and 50.32 years, respectively.

The mean (T2 – T1) was 1.86 years, and the (T3 – T2) was 35.25 years. Lateral cephalograms were used to perform profile facial silhouettes, and an online evaluation was performed by 72 laypeople, 63 dentists, and 65 orthodontists, rating the attractiveness from 1 (least attractive) to 10 (most attractive). The intragroup comparison was performed with the repeated measures analysis of variance and Tukey tests. Intergroup comparison was performed with t tests, 1-way analysis of variance, and Tukey tests. Results: The E group had a longer treatment time than that of the NE group. In the pretreatment, posttreatment, and long-term posttreatment stages, the E and NE groups showed similar profile attractiveness. Laypersons and dentists were more critical than orthodontists. At long-term posttreatment follow-up, profile attractiveness was similar in patients treated with and without extractions.

Reference:

Bravo Vallejo G, Alcaraz Ros GD, Peloso RM, Gambardela-Tkacz CM, Cotrin P, Freitas KMS, de Freitas MR. Long-term profile attractiveness of patients with Class I and II malocclusion treated with and without extractions: A 35-year follow-up. Am J Orthod Dentofacial Orthop. 2024 Jan 16:S0889-5406(23)00661-3. doi: 10.1016/j.ajodo.2023.11.009. Epub ahead of print. PMID: 38231168.

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Prenatal exposure to antiseizure medication topiramate may not increase risk of autism spectrum disorder among kids: NEJM

Topiramate is an antiseizure medication prescribed to treat epilepsy as well as migraines and bipolar disorder.

Researchers at  Harvard T.H. Chan School of Public Health have found in a new research that Prenatal exposure to antiseizure medication topiramate may not increase children’s risk of autism spectrum disorder. 

The study has been published in the New England Journal of Medicine.

Many studies have examined the neurodevelopmental impacts of prenatal exposure to valproate and lamotrigine, two other antiseizure medications commonly taken by people living with epilepsy. Most of these studies have linked valproate to a heightened risk of ASD among children exposed to it prenatally but have found no additional risk linked to lamotrigine. Research into the neurodevelopmental safety of topiramate, meanwhile, has been limited, with mixed findings.

“Our findings provide needed clarity on the possible neurodevelopmental impacts of this commonly used drug,” said lead author Sonia Hernández-Díaz, professor of epidemiology. “While our primary analyses focused on mothers with epilepsy, the study has implications for moms and moms-to-be who live with other conditions treated by topiramate as well.”

Using data recorded between 2000 and 2020 across two U.S. health care databases, the researchers identified a population-based cohort of nearly 4.3 million pregnant women and their children. Children who had been exposed to topiramate during the second half of pregnancy were compared with children who had never been exposed to an antiseizure medication prenatally, with respect to the risk of ASD. Children who had been exposed to valproate and lamotrigine during the second half of pregnancy were used as control groups.

The study found that at age 8, children born to mothers with epilepsy had a higher prevalence of ASD compared to children in the general population. Within the full study population, 1.9% of children who had never been prenatally exposed to an antiseizure medication were diagnosed with ASD. For children born to mothers with epilepsy, the incidence was 4.2% with no exposure to an antiseizure medication; 6.2% with exposure to topiramate; 10.5% with valproate; and 4.1% with lamotrigine. However, after adjusting for confounding variables, the researchers concluded that prenatal exposure to topiramate and lamotrigine was no longer associated with additional risk of developing ASD, while prenatal exposure to valproate remained associated with additional risk.

The researchers noted that this relationship between valproate and ASD is dose-dependent, and that while topiramate appears safe from a neurodevelopmental standpoint, it remains linked with a higher risk of oral clefts. They also noted certain limitations of the study, including a substantial portion of children in the study population being lost to follow up before age 8.

Reference:

Sonia Hernández-Díaz, Loreen Straub,  Brian T. Bateman, Yanmin Zhu, Helen Mogun, Katherine L. Wisner, Kathryn J. Gray, Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure, New England Journal of Medicine, DOI: 10.1056/NEJMoa2309359.

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Cranberries provide runners with all-natural boost, according to new research

Competitive athletes are always looking for an extra edge that can help them improve performance. According to a new study by Concordia researchers published in the journal Physical Activity and Nutrition, they can find one in the common cranberry.

In a series of trials involving trained distance runners, the researchers found that ingesting a cranberry supplement for 28 consecutive days led to noticeable improvements in both performance and muscle fatigue following 1,500-metre time trials. Reoxygenation rates were faster and running speeds improved by 1.5 per cent.

“When it comes to elite athletes, any advantage can make the difference between finishing fifth or on the podium,” says Andreas Bergdahl, an associate professor in the Department of Health, Kinesiology and Applied Physiology and the paper’s senior author.

Effects of different energy systems

The researchers recruited 14 high-level runners from Concordia’s varsity track and field team and from two Montreal running clubs, who are performing at least five hours of endurance training a week.

The athletes ran two time trials over three separate visits, one a 1,500-metre, the other a 400-metre. The first visit was used as a baseline. At the second, they were given a single large dose of cranberry extract two hours before running. The athletes were then instructed to consume a small dose of cranberry extract daily for 28 days, after which they repeated the runs for a third time.

“We selected these distances to test the effects the cranberry extract had on different energy systems,” says Francis Parenteau, a PhD candidate and the paper’s lead author. “The 400-metre is shorter and of higher intensity and involves the anaerobic system. The 1,500-metre uses the aerobic system but is shorter than what the athletes usually run. Since they do not train to run that distance, we were able to isolate training effects as a variable.”

Besides their running time, the researchers measured their post-exercise blood lactate, a marker for potential muscle fatigue and lack of oxygen. They also attached a portable near-infrared spectroscopy device to the runners to measure muscle oxygenation levels before, during and after their runs.

Following data analysis, the researchers found that 28 days of cranberry extract consumption demonstrated a trend toward increased speed in the 1,500-metre time trial but not in the 400-metre. However, they did notice that lactate buildup was reduced following the 400-metre but not the 1,500-metre compared to baseline.

The data also indicated that the cranberry extract promoted better oxygen extraction by the muscle, improved lactate clearance and slower muscle deoxygenation.

A runner’s best friend, made in Quebec

Cranberries are extraordinarily rich in polyphenols, a natural compound with antioxidant properties. These characteristics help protect the body from the harmful effects of free radical molecules produced by strenuous exercise.

Cranberries are also indigenous to and a major industrial crop for Quebec. The province produces roughly 60 per cent of Canada’s cranberry yield, according to Statistics Canada.

“The beauty of this is that it is all natural,” says Bergdahl. “It is an ergogenic aid, meaning that it is performance-enhancing, but it is not an anabolic steroid. Athletes can get this important boost in their performance just by consuming more cranberries.”

Reference:

Parenteau F, Puglia VF, Roberts M, Comtois AS, Bergdahl A. Cranberry supplementation improves physiological markers of performance in trained runners. Phys Act Nutr. 2023 Dec;27(4):8-14. doi: 10.20463/pan.2023.0032. 

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Mammography-based AI model can predict 5-year breast cancer risk: Study

USA: Duke University researchers have developed an artificial intelligence (AI) model that can predict five-year breast cancer risk from mammograms, according to a study published in Radiology.

The researchers revealed that their deep learning-based algorithm, a simplified offshoot of Mirai, performed well in predicting cancer risk by evaluating breast asymmetry features on mammograms.

“Localized bilateral dissimilarity, an imaging marker for breast cancer risk, approximated the predictive power of Mirai and was a key to Mirai’s reasoning,” the study stated.

While attending regular screening mammogram appointments is crucial in reducing the risk of dying from breast cancer, pinpointing which women face a higher risk of developing the disease can be tricky.

AI can be helpful in this area. Mirai is a deep learning-based algorithm that has shown that it can help predict breast cancer. However, not much is known about Mirai’s reasoning process. The researchers cautioned that with this in mind, the algorithm could be relied on too heavily by radiologists and lead to incorrect diagnoses.

Jon Donnelly, Duke University, Durham, NC, and colleagues aimed to identify whether bilateral dissimilarity underpins Mirai’s reasoning process. For this purpose, they developed AsymMirai, which they highlighted is easier and simpler to understand than Mirai.

The algorithm was built on the front-end deep learning portion of Mirai and was developed with local bilateral dissimilarity as an interpretable module. This module examines tissue differences between the left and right breasts.

The researchers compared 210,067 mammograms from 81,824 patients in the EMBED (EMory BrEast imaging Dataset) from 2013 to 2020 using both Mirai and AsymMirai models.

Pearson correlation coefficients were computed between the risk scores of Mirai and AsymMirai. Subgroup analysis was performed in patients with consistent AsymMirai’s year-over-year reasoning. Mirai and AsymMirai risk scores were compared using the area under the receiver operating characteristic curve (AUC).

The study included screening mammograms (n = 210 067) from 81,824 patients (mean age, 59.4 years).

The study revealed the following findings:

  • Deep learning–-extracted bilateral dissimilarity produced similar risk scores to those of Mirai (1-year risk prediction, r = 0.6832; 4–5-year prediction, r = 0.6988) and achieved similar performance as Mirai.
  • For AsymMirai, the 1-year breast cancer risk AUC was 0.79 (Mirai, 0.84), and the 5-year risk AUC was 0.66 (Mirai, 0.71).
  • In a subgroup of 183 patients for whom AsymMirai repeatedly highlighted the same tissue over time, AsymMirai achieved a 3-year AUC of 0.92.

“The study represents not a potential contribution of artificial intelligence to the existing body of knowledge in breast cancer risk prediction assessment,” Vivianne Freitas, MD, from the Joint Department of Medical Imaging in Toronto, Canada, wrote in an accompanying editorial.

Along with that, it shows that AI models “can be understandable and effective, serving as a bridge and narrowing the divide between the intricate world of AI algorithms and their real-world clinical application,” she wrote.

Reference:

Donnelly J, Moffett L, Barnett AJ, Trivedi H, Schwartz F, Lo J, Rudin C. AsymMirai: Interpretable Mammography-based Deep Learning Model for 1-5-year Breast Cancer Risk Prediction. Radiology. 2024 Mar;310(3):e232780. doi: 10.1148/radiol.232780. PMID: 38501952.

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Apple Cider Vinegar Shows Promise as Weight Loss Aid, finds Study

Recently, there has been increasing interest in alternative remedies to support weight management, and one such remedy that has gained popularity is apple cider vinegar.

A recent study conducted in Lebanon aimed to investigate the potential benefits of ACV consumption on weight reduction and metabolic health parameters. This study was published in the journal of BMJ Nutrition Prevention & Health by Rony A. and colleagues.

Obesity and overweight are significant global health challenges associated with various adverse health outcomes, including cardiovascular disease, diabetes, and metabolic syndrome. Natural remedies, such as ACV, have garnered attention for their purported weight loss benefits.

The study recruited 120 overweight and obese individuals who were randomly assigned to different doses of ACV or a placebo over a 12-week period. Anthropometric measurements, fasting blood glucose, triglyceride, and cholesterol levels were assessed at multiple time points throughout the study.

Key Findings:

  • Participants consuming ACV experienced significant reductions in anthropometric variables, including weight, body mass index (BMI), waist/hip circumferences, and body fat ratio.

  • ACV consumption also led to improvements in metabolic parameters, including blood glucose, triglyceride, and cholesterol levels.

  • No significant adverse effects were observed during the 12-week period of ACV intake.

The study concludes that daily consumption of ACV is associated with favorable effects on both anthropometric and metabolic parameters in individuals with overweight and obesity. ACV emerges as a promising antiobesity supplement without apparent side effects.

These findings suggest that ACV could be considered as part of a comprehensive approach to weight management in individuals struggling with overweight and obesity. However, further research is warranted to confirm these results and explore the mechanisms underlying the observed effects of ACV on weight reduction and metabolic health.

Reference:

Abou-Khalil, R., Andary, J., & El-Hayek, E. Apple cider vinegar for weight management in Lebanese adolescents and young adults with overweight and obesity: a randomised, double-blind, placebo-controlled study. BMJ Nutrition, Prevention & Health,2024;e000823. https://doi.org/10.1136/bmjnph-2023-000823

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