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New Delhi: After oncologists raised concerns about his recent claim that a strict diet helped his wife overcome stage 4 cancer, Congress leader Navjot Singh Sidhu on Monday informed that his wife underwent surgeries, chemotherapy, hormonal and targeted therapy, in addition to following a strict diet plan inspired by ancient Indian Ayurveda to support her cancer treatment.
During a press conference in Amritsar on November 21, Sidhu stated that his wife Navjot Kaur Sidhu had been declared cancer-free, emphasizing the role of dietary and lifestyle changes in her recovery.
However, oncologists at Tata Memorial Hospital, Mumbai warned that cancer patients should not delay or stop their treatment by following unproven remedies.
In a video message posted on X on Monday, Sidhu said, “I want to say that a doctor is like God to me, and doctors have always been my priority. I have a doctor (Navjot Kaur Sidhu) at home. Whatever we have done was done with the consultation of doctors in a collaborative process.”
Also Read:Sidhu claims Diet Changes Cured His Wife’s Cancer, doctors warn against unscientific remedies
According to the PTI report, the former Punjab Congress chief also shared the diet plan and wrote, “My wife’s cancer journey involved surgeries, chemotherapy, hormonal and targeted therapy, positivity and determination to fight cancer which was facilitated by a strict diet plan inspired by Indian Ayurveda, the nobel prize winning research of Yoshinori Ohsumi for discoveries of the mechanisms autophagy and observation of eminent doctors worldwide.”
The diet chart included lemon water, turmeric, apple cider vinegar, walnuts, juice made from beetroot, carrot, and amla, among other items. She also consumed neem leaves, but sugar, dairy products and wheat were removed from her diet, he said.
Sidhu also mentioned that his wife was given water with a pH level of seven.
Sidhu quoted an old saying — ‘jaisa ann, waisa mann, waisa tann’ (as is the food, so is the mind and body), and added, “Consider this diet chart as facilitation in the treatment.”
“My mother used to say ‘Vasudhaiva Kutumbakam’ (the whole world is my family). We want to share the benefits we receive with everyone,” he said.
Speaking about her experience, Navjot Kaur Sidhu said it was difficult for her to follow the diet initially but she stated to feel good after a few days.
“I began losing weight, and the swelling started reducing. I have lost 30 kg. Somewhere, the Ayurvedic diet benefitted me a lot,” she said.
On November 23, Dr C S Pramesh, Director of Tata Memorial Hospital, posted a video of Sidhu’s press conference on X and said, “Parts of the video imply that starving cancer by avoiding dairy products and sugar, and consuming haldi (turmeric) and neem, helped cure her ‘incurable’ cancer.”
He added, “Please don’t believe or be fooled by these statements, regardless of who they come from. These are unscientific and baseless recommendations. It was surgery and chemotherapy, which are evidence-based treatments, that made her cancer-free, not haldi, neem, or other such remedies.”
Also Read:Fact Check: Sidhu’s video claiming neem leaves, turmeric, apple vinegar, lemon vinegar and intermittent fasting can cure cancer is false and misleading
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New Delhi: While responding to a Right to Information (RTI) application, the Delhi Medical Council (DMC) has clarified that dentist(s) are not qualified to do aesthetic procedures like Botox or Acne treatment.
Further, the Council specified that in order to practice allopathy in Delhi, a person should have an M.B.B.S degree and a registration with the council. Any person, not having the requisite medical qualification and council registration is liable to be prosecuted, the Medical Council in the National capital further mentioned.
The RTI, a copy of which is with Medical Dialogues team, was filed on 30 October, 2024 and it sought clarification from the medical council regarding the eligibility of dentists to perform such aesthetic procedures.
Responding to the RTI, DMC on 20.11.2024 mentioned, “With reference to your application received in this office on 30. October, 2024, on the subject noted above; based on the records available in the office of the Delhi Medical, it is informed that the dentist(s) is/are not qualified to do medical procedure like Botox, treating acne etc.”
“It is further informed that for practicing allopathic system of medicine in the NCT of Delhi, a person should hold recognized medical qualification as per the Schedule to the NMC Act and should be registered with the Delhi Medical Council; hence, a person being a holder of M.B.B.S. qualification and registered with the Delhi Medical Council can practice modem scientific system of medicine (allopathy) in the NCT of Delhi,” the Council added.
It further informed that any person, who is found to be practicing modem scientific system of medicine (allopathy) in the NCT of Delhi without holding any requisite medical qualification as per the Schedule to the NMC Act and not registered with the Delhi Medical Council, “is liable to be prosecuted in terms of the Section 27 of the Delhi Medical Council Act, 1997.”
Section 27 of the DMC Act, 1997 states the following:
“27. False assumption of Medical Practitioner or Practitioner under this Act to be an offence.—Any person who falsely assumes that he is a medical practitioner or practitioner as defined in Clause (7) of Section 2 and practises the modern scientific system of medicine, shall be punishable with rigorous imprisonment which may extend up to three years or with fine which may extend up to Rs. 20,000 or with both.”
DMC in the RTI response also asked people that they may file complaint against any person, practicing modern scientific system of medicine (allopathy) in the NCT of Delhi without holding any requisite medical qualification as per Schedule to the NMC Act and not registered with Delhi Medical Council, to the Council in the following address:
“Delhi Medical Council, Ground Floor, B-Wing, Block-1, DMRC IT Park. Shastri park, New Delhi- 110053”
The complainants will have to give details of the
(a) name, description and address of the complainant
(b) the name, description and address of the individual who is found alleged to be practicing medicine without holding any requisite qualification
(c) documents in support of the complaint, if any i.e. Prescription, Letter Pad of the clinic, Visiting Card of the medical practitioner etc.
They may also send the complaint to the Anti-Quackery Cell, Directorate General of Health Services, Govt. of NCT of Delhi, Swasthya Sewa Nideshalaya Bhawan, F-17, Karkardooma, Delhi-110032
Meanwhile, sharing a copy of the RTI response on his X (formerly Twitter) account, Dr. Lakshya Mittal, the President of the United Doctors’ Front Association (UDFA) wrote, “RTI reply from Delhi Medical Council #DMC confirms dentists are not qualified to perform aesthetic procedures like Botox or acne treatment. Yet, many continue to do so, misleading patients through social media.”
“If any such influencer comes across, please file a complaint with the DMC or Anti-Quackery Cell. Let’s uphold ethical medical practices,” he further added.
Earlier, UDFA had raised the issue of a homeopathic practitioner in Jind performing allopathic procedures including aesthetic surgeries such as Botox, Fillers etc. Back then, the association had urged the Haryana Government authorities to conduct immediate investigations and take strict action against the concerned homeopathic doctor.
Medical Dialogues had earlier reported that back in 2022, the National Medical Commission (NMC) had ordered a crackdown on the mushrooming practice of unethical and illegal aesthetic surgeries including hair transplant. The Apex Medical Commission had clarified at that time that only properly trained licensed registered medical practitioners (RMPs) i.e. practitioner of modern medicine are eligible for conducting such procedures.
Issuing guidelines, the Ethics and Medical Registration Board (EMRB) of NMC had recommended MCh/DNB Plastic surgery, MD/DNB Dermatology with adequate grooming in dermatological surgical procedures for conducting hair transplantation surgeries.
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Chandigarh: Dr Digambar Behera, Professor Emeritus at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, assumed the role of President of the National Academy of Medical Sciences (NAMS) on Saturday.
Dr Behera has taken charge of the coveted post from Dr S K
Sarin, the outgoing President, during a convocation function at the
AIIMS, Jodhpur.
The 64th convocation and annual scientific conference of NAMS is being
organized on 23rd-24th November at All India Institute of Medical Sciences,
Jodhpur, Rajasthan. According to a statement here, Dr Behera will remain
president of NAMS for three years, reports PTI.
Dr Behera said he is proud to occupy this position which was earlier held
by legendary medical personalities of the country. “I will try to keep up the
traditions of the academy and will work and see that NAMS contributes further
to the medical education, research, and health care delivery in the country,” he
said.
A renowned pulmonologist, Behera is currently the Director
of Pulmonary Medicine and Critical Care Medicine at Fortis Hospital,
Mohali, Punjab, and an advisor to the Task Force for National TB Elimination
program of India. For his contributions in the domain of Medical Sciences,
the Odisha Bigyan Academy conferred on Prof (Dr) Digambar Behera the Biju
Patnaik Award for Scientific Excellence for the year 2016. He also received
various other prestigious honours such as Padma Shri (2020), PRJ Gangadharam
Award (2015), Kael Styblo Prize for Public Health (2009), and BC Roy Award
(2004).
Prof (Dr) Digambar Behera is a highly regarded Physician and Researcher in Respiratory Medicine. Born in Cuttack District in 1953, Prof Behera received his MBBS from SCB Medical College, Cuttack, MD from PGIMER, Chandigarh, and MNAMS qualification in General Medicine and Respiratory Medicine. He was former dean (research) and head of pulmonary medicine department at PGIMER, Chandigarh.
He also worked as Director of the LRS Institute of Tuberculosis and Respiratory Diseases, New Delhi, for about 6 years. In his research career spanning over 35 years, Prof Behera has published nearly 500 papers in reputed
journals, nearly 90 papers in international conferences, and about 80 papers in
national conferences. His papers have enjoyed high citations and Impact
factors. He has written chapters in about 40 texts and reference books and
authored/edited several books.
He has supervised the thesis works of many Ph.D. and D.M./M.D. scholars. Prof. Behera has received many awards and recognitions from within the country and abroad for his work in areas including tuberculosis,
lung cancer, COPD, asthma, and other respiratory diseases.
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An alternative low-density
lipoprotein (LDL) cholesterol-lowering strategy can successfully reduce the
risk of atherosclerotic cardiovascular diseases (ASCVD) instead of
high-intensity statins due to the additional benefits of decreased diabetic
risk and statin tolerance, as per the results published in the journal JAMA
Cardiology.
For high-risk patients with
atherosclerotic cardiovascular disease (ASCVD), intensive lowering of
low-density lipoprotein (LDL) cholesterol levels is advised. High-intensity
statins are the recommended first-line treatment for such conditions. However,
high-intensity statins can have some side effects and lead to poor long-term
adherence. The previous literature suggested a combination of
moderate-intensity statin with LDL cholesterol-lowering drugs to reduce the
side effects and improve tolerance. Most of the previous research has explored
the impact of such a combination on preventing adverse cardiovascular events.
As there is limited research on the effects of LDL cholesterol-lowering drugs
on effectiveness and safety, researchers conducted a systematic review and
meta-analysis on the long-term efficacy and safety of an alternative LDL
cholesterol–lowering strategy vs. high-intensity statin strategy in patients
with ASCVD in randomized clinical trials.
A literature search was carried
out from databases like PubMed, Embase, and other websites (ClinicalTrials.gov,
European Society of Cardiology, tctMD) to include randomized clinical
trials comparing an alternative LDL cholesterol–lowering strategy vs. a
high-intensity statin strategy in patients with ASCVD, with the presence of
cardiovascular events as endpoints. Many studies were filtered, and two trials
were deemed eligible. They were the RACING trial and the LODESTAR trial. The
moderate-intensity statin with ezetimibe combination therapy in the RACING
trial and the treat-to-target strategy in the LODESTAR trial were classified as
alternative LDL cholesterol-lowering strategies. The primary endpoint was
to assess a 3-year composite of all-cause death, myocardial infarction, stroke,
or coronary revascularization, while the secondary endpoints comprised clinical
efficacy and safety endpoints.
Findings:
Thus, the study concluded that an
alternative LDL cholesterol-lowering strategy has a comparable efficacy
regarding mortality or adverse cardiovascular events in ASCVD patients.
Additionally, it also exhibited a reduction in LDL cholesterol levels and risk
for new-onset diabetes and intolerance.
Further reading: Lee Y, Hong
B, Yun KH, et al. Alternative LDL Cholesterol–Lowering Strategy vs
High-Intensity Statins in Atherosclerotic Cardiovascular Disease: A
Systematic Review and Individual Patient Data Meta-Analysis. JAMA
Cardiol. Published online November 20, 2024.
doi:10.1001/jamacardio.2024.3911
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Netherlands: A recent prospective study demonstrated that the use of a leadless pacemaker capable of wireless communication with a subcutaneous implantable cardioverter-defibrillator (ICD) was free of pacemaker-related major complications. Additionally, the study confirmed successful communication between the devices and stable pacing thresholds maintained for up to six months.
The findings were published online in the New England Journal of Medicine.
The subcutaneous implantable cardioverter-defibrillator (ICD) is known to have fewer lead-related complications compared to a transvenous ICD but cannot provide bradycardia and antitachycardia pacing. To address this limitation, Reinoud E. Knops, Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands, and colleagues aimed to evaluate the safety of a modular pacing-defibrillator system combining a leadless pacemaker with a subcutaneous ICD, enabling wireless communication to deliver these pacing functions.
For this purpose, the researchers conducted a multinational, single-group study enrolling patients at risk for sudden death due to ventricular arrhythmias. Participants were monitored for six months following the implantation of a modular pacemaker-defibrillator system.
The safety endpoint was defined as freedom from major complications related to the leadless pacemaker, with a performance goal of 86%. The two primary performance endpoints were the successful communication between the pacemaker and the ICD, set against a performance goal of 88%, and maintaining a pacing threshold of up to 2.0 V at a 0.4-msec pulse width, with a performance goal of 80%.
The key findings of the study were as follows:
“The leadless pacemaker, wirelessly communicating with a subcutaneous ICD, surpassed performance targets for major complication-free outcomes, successful device communication, and the proportion of patients achieving a pacing threshold of up to 2.0 V at a 0.4-msec pulse width over 6 months,” the researchers concluded.
Reference: Knops RE, Lloyd MS, Roberts PR, Wright DJ, Boersma LVA, Doshi R, Friedman PA, Neuzil P, Blomström-Lundqvist C, Bongiorni MG, Burke MC, Gras D, Kutalek SP, Amin AK, Fu EY, Epstein LM, Tolosana JM, Callahan TD, Aasbo JD, Augostini R, Manyam H, Nair DG, Mondésert B, Su WW, Pepper C, Miller MA, Grammes J, Saleh K, Marquie C, Merchant FM, Cha YM, Cunnington C, Frankel DS, West J, Matznick E, Swackhamer B, Brisben AJ, Weinstock J, Stein KM, Reddy VY, Mont L; MODULAR ATP Investigators. A Modular Communicative Leadless Pacing-Defibrillator System. N Engl J Med. 2024 Oct 17;391(15):1402-1412. doi: 10.1056/NEJMoa2401807. Epub 2024 May 18. PMID: 38767244.
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Saudi Arabia: A recent study, published in the Journal of Diabetes and its Complications has identified key predictors of liver fibrosis progression in individuals with type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD).
Researchers found that an increase in alkaline phosphatase (ALP) levels, an increase in waist circumference, and a reduction in platelet count were significant indicators of worsening liver fibrosis in these patients. The study also highlighted the potential protective role of GLP-1 receptor agonists in slowing liver fibrosis progression.
As liver fibrosis can lead to cirrhosis and increase the risk of liver-related complications, understanding factors that contribute to its progression is critical for improving patient outcomes. Assim A. Alfadda, Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia, and colleagues aimed to examine the factors that predict liver fibrosis progression in patients with T2DM over a minimum follow-up period of three years.
For this purpose, the researchers followed 233 patients whose clinical, laboratory, and liver FibroScan data were analyzed at the end of the study period. The patients were divided into two groups: 42 progressors (18.0%) who experienced liver fibrosis progression, and 191 non-progressors (82.0%). Factors influencing fibrosis progression were identified by comparing the characteristics of these two groups.
Based on the study, the researchers reported the following findings:
“In patients with type 2 diabetes, higher alkaline phosphatase, increased waist circumference, and lower platelet count were predictive of liver fibrosis progression. Progressors exhibited elevated ALP levels and decreased platelet count, while non-progressors showed improvements in waist circumference and glycosylated hemoglobin. Notably, the use of GLP-1 receptor agonists was associated with a reduced risk of liver fibrosis progression,” the researchers reported.
“The study reinforces the importance of monitoring specific clinical markers—such as ALP levels, waist circumference, and platelet count—in predicting liver fibrosis progression in T2DM patients with MASLD. The findings also highlight the promising potential of GLP-1 receptor agonists as a protective treatment, offering hope for more effective management of both diabetes and liver health,” they concluded.
Reference:
Alfadda, A. A., Alqutub, A. N., Sherbeeni, S. M., Aldosary, A. S., Alqahtani, S. A., Isnani, A., Gul, R., Khaleel, M. S., Alqasim, S. M., & Almaghamsi, A. M. (2024). Predictors of liver fibrosis progression in cohort of type 2 diabetes mellitus patients with MASLD. Journal of Diabetes and its Complications, 108910. https://doi.org/10.1016/j.jdiacomp.2024.108910
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A new study published in the New England Journal of Medicine showed that antibiotic therapy for 7 days was not inferior to treatment for 14 days among patients hospitalized with bloodstream infections. An estimated 2.9 million people worldwide die from bloodstream infections each year, making it one of the most serious forms of bacterial diseases. Although the recommended period of antibiotic therapy is 14 days or more, nothing is known about how long it should last for bloodstream infections. Shorter antibiotic treatments raise the possibility of clinical failure or infection recurrence.
The BALANCE Investigators from the University of Toronto decided to find out if the mortality rates following 7 and 14 days of antibiotic use were comparable. Also, they expected that shortened antibiotic duration might lower adverse events, antibiotic exposure, and resistant organism infections.
This research randomly allocated hospitalized patients with bloodstream infections, including the ones in the intensive care unit [ICU], to receive antibiotic therapy for 7 or 14 days. The treating team made decisions about the choice, dosage, and route of antibiotics. The patients with severe immunosuppression, foci that needed ongoing care, single cultures that could have been contaminated, or cultures that produced Staphylococcus aureus were not included. With a noninferiority margin of 4 percentage points, the main outcome was mortality from any cause within 90 days after the bloodstream infection diagnosis.
The intention-to-treat analysis comprised a total of 3608 randomly assigned patients from 74 hospitals across 7 countries where 1814 patients received antibiotic therapy for 7 days, and 1794 patients received antibiotic treatment for 14 days. 45.0% of patients were on hospital wards and 55.0% were in the intensive care unit at the time of inclusion. 75.4% of infections were contracted in the community, 13.4% in hospital wards, and 11.2% in intensive care units.
The urinary tract (42.2%), abdomen (18.8%), lung (11.0%), vascular catheters (6.3%), and skin or soft tissue (5.2%) were the most frequent sites of bacteremia. By 90 days, 286 patients (16.1%) who had received antibiotics for 14 days and 261 patients (14.5%) who had received antibiotics for 7 days had passed away, demonstrating that the shorter treatment time was not inferior.
10.7% of patients in the 14-day group and 23.1% of patients in the 7-day group received treatment for longer than the allotted amount of time. Overall, antibiotic therapy for 7 days was comparable to treatment for 14 days in hospitalized patients with bloodstream infections.
Source:
(2024). Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections. In New England Journal of Medicine. Massachusetts Medical Society. https://doi.org/10.1056/nejmoa2404991
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Roflumilast may effectively reduce symptoms and flare-ups in recurrent aphthous stomatitis, suggests study published in the International Journal of Dermatology.
Severe recurrent aphthous stomatitis (RAS) represents a therapeutic challenge because of its impact on the patient’s quality of life. Additionally, no approved systemic therapies are available. Roflumilast, a phosphodiesterase-4 inhibitor, has shown promise in other inflammatory dermatological conditions. This study aimed to assess the characteristics, effectiveness, and safety of roflumilast in treating RAS in routine clinical practice. This is a single cohort ambispective observational study conducted in five Spanish centers. Twenty-two patients with RAS treated with roflumilast participated. Data collection included demographic, clinical, and outcome variables. Statistical analysis compared the outcomes of 12 weeks of roflumilast treatment with a similar prior period without treatment. Results: During treatment with roflumilast, a significant reduction in flare-ups (88%) and oral ulcers (94%) was observed compared to the untreated period. A reduction in pain (66%) and ulcer duration (63%) was observed. Adverse effects (AEs) occurred in 13 patients, predominantly headache and gastrointestinal disturbances. Most of these were self-limiting or manageable with dose adjustment. Treatment was withdrawn in three cases, mainly because of AEs.
This study suggests that roflumilast may effectively treat RAS by reducing the number of flare-ups and ulcers, their duration, and the symptomatology produced by the ulcers. In addition, roflumilast has a good safety profile, is well tolerated at low doses, and does not require close monitoring. These characteristics and its favorable economic profile make roflumilast a promising therapeutic option in this pathology.
Reference:
Peñuelas Leal, R., Bagan, L., Grau Echevarría, A., Peñuelas Ruiz, J.A., Zaragoza Ninet, V., Sánchez Carazo, J.L., Pérez Pastor, G., Labrandero Hoyos, C., Finello, M., Martínez Fernández, S., Blaya Imbernon, D., González García, Á., Pérez Zafrilla, E., Martí Cabrera, M. and Bagan, J. (2024), Treatment of recurrent aphthous stomatitis with oral roflumilast, a multicenter observational study. Int J Dermatol. https://doi.org/10.1111/ijd.17478
Keywords:
Roflumilast, may, effectively, reduce, symptoms, flare-ups, recurrent, aphthous, stomatitis, suggest, study, International Journal of Dermatology, Peñuelas Leal, R., Bagan, L., Grau Echevarría, A., Peñuelas Ruiz, J.A., Zaragoza Ninet, V., Sánchez Carazo, J.L., Pérez Pastor, G., Labrandero Hoyos, C., Finello, M., Martínez Fernández, S., Blaya Imbernon, D., González García, Á., Pérez Zafrilla, E., Martí Cabrera, M. and Bagan, J.
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In 1896, in his seminal work “The Cell in Development and
Inheritance”, the cell biologist Edmund B. Wilson formulated a concept that was
destined to shape early 20th-century embryology and cell biology:
“embryogenesis begins during oogenesis”. Condensed research on cellular
biology, cytology, and embryonic development, he ultimately elaborated on how
oogenesis lays the foundations of early embryogenesis. Indeed, it became
progressively apparent that, during its growth and maturation, the oocyte
actively implements a development plan for future embryogenesis by stockpiling
key vital materials, such as maternal RNAs, proteins, and organelles. These
factors will direct the early phases of cell division, gene expression, and
cell specification, well before the activation of the zygote’s genome. In this
view, oogenesis and embryogenesis are therefore a continuum. The foundational
role of the oocyte in development was initially demonstrated in model species
characterized by very large egg cells and/or external fertilization, such as
Drosophila, Caenorhabditis and Xenopus. Studying other organisms has been more challenging;
it has been so long believed that mammalian species were unaffected by this
phenomenon, due to the early maternal support to embryo development. In fact,
the mammalian oocyte undergoes a spectacular 700-fold increase in volume during
growth from the primordial to the preovulatory stage, suggesting a need for
accumulation of cellular mass, proteins and RNAs in preparation for early
development. IVF techniques have revolutionized research in mammalian
embryology, allowing thorough investigation of the oocyte legacy in development.
To sustain protein synthesis during early mammalian
development, at least two conditions can justify the use of maternal mRNAs
accumulated throughout oogenesis: i) the condensation and silencing of the
maternal chromatin shortly before meiotic resumption at ovulation; II) the absence
of major transcription of the embryonic genome during the first cleavage
cycles. Therefore, during early embryogenesis, synthesis of new proteins
largely depends on maternal factors (mRNA, microRNAs, and small interfering
RNAs), which are then progressively replaced by embryonic transcripts. This
exposes the embryo to the risk that defects in quantity and quality of RNAs produced
during oogenesis affects the early cleavage stages, with potentially fatal
consequences for embryo development.
Likewise, maternal proteins can also be stored during
oogenesis and used from meiotic resumption until the early cleavage stages,
while the maternal or embryonic genome remain silent. One of the first
described genes of maternal origin showing an embryonic effect (referred to as
maternal effect genes, MEGs) is MATER. In the human, biallelic mutations in
MATER that cause decreased protein synthesis in oocytes are found in infertile
women whose embryos arrest at the first cleavage stages. Together with other MEGs
products, MATER shares a common and well-defined cell localization. These
factors are organized in the subcortical maternal complex (SCMC), a protein
aggregate distributed below the oocyte cortex and inherited by early embryos.
The SCMC is involved in the regulation of multiple processes including meiotic
spindle formation and positioning, regulation of translation, organelle
redistribution, embryonic cleavage and epigenetic reprogramming. Notably, the
unique localization of the SCMC suggests that not only is the correct
expression of MEG-encoded proteins essential for early development, but also that
the spatial arrangement of such factors may be finely regulated.
Another example of MEG, not associated to the SCMC, is
TUBB8. The product of this gene is a specific β‐tubulin isotype present only in
primates and exclusively found in oocytes, where it operates as the major
structural component of the meiotic spindle. As such, TUBB8 is essential for
ensuring cytoskeletal functions required for the completion of meiosis during
fertilization and the correct accomplishment of the first mitotic divisions.
Defective variants of TUBB8 detected in Journal Pre-proof 3 infertile women
produce disruptive spindle‐assembly deficiencies during oocyte maturation and
fertilization, as well as cleavage aberrations and arrest in early embryos.
Possible paternal effects on embryo development and newborn
health are less defined and mainly associated with the sperm chromosome and
centriolar constitution, due to the relative cellular contribution of the
oocyte and sperm to the formation of the zygote. However, recent studies
suggest that paternal factors in the form of RNAs may support early embryo
development. In the mouse, several microRNAs are delivered to the sperm during
post-testicular maturation and transit from the caput to the cauda of the
epididymis. ICSI embryos generated with sperm collected from caput epididymis
show diverse overexpressed regulatory factors, implant poorly and undergo postimplantation
arrest. However, molecular and developmental defects of such embryos are completely
rescued by microinjection of purified cauda-specific small RNAs. Further
evidence on the role of sperm-derived small RNAs in shaping embryo development
and offspring health is growing and will probably be soon extended to human
infertility.
Overall, investigations on possible genetic causes of early
developmental failure are progressively revealing the key role of maternally –
and, to a less extent, paternally – inherited factors. Mutations affecting such
factors can impair crucial regulatory networks and cause developmental arrest
at any stage between fertilization an implantation. This influence likely
extends beyond implantation, with a significant phenotypic spectrum ranging
from preimplantation arrest to imprinting disorders in newborns. This
highlights the clinical utility of such investigations, not only in preventing
prolonged infertility but also in informing carrier couples about potential
obstetrical and neonatal risks.
So far, classical single-gene association studies have been
instrumental to generate these notions, offering a diagnostic explanation to
selected cases of reproductive failure and initial insights in the genetics
governing early human development. This has made assessment of genetic risk in
reproduction already possible, although mainly in relation to monogenic traits.
But, similar to other medical disciplines, novel more accessible genome‐wide
sequencing and analysis techniques are bringing about a revolution in the
genetics of infertility. The ability to screen thousands of genes with a
predicted role in gamete competence and embryo development at the preconception
stage is now technically feasible and available at sustainable costs. Carrier
screening for recessive genetic disorders has become commonplace in many IVF
settings, representing the most established and validated application of
preconception genomics. The field is rapidly transitioning from gene-panel to
exome sequencing-based approaches, enabling a more comprehensive genomic
assessment of key genes involved in reproductive risk, as well as infertility
and embryonic lethality.
To fully realize the potential of preconception genomic
medicine, further efforts should focus on the development of large biobanks
combining genomic data with well-curated electronic medical records (EMR) in
infertility. Genome-wide association studies will then have the potential to generate
several outcomes: to shed light on the relationship between biological
mechanisms and phenotype, to enhance the precision of infertility diagnosis, to
assess the genetic risk of prospective parents toward prenatal and postnatal
complications, and to better inform clinical strategies and the development of
personalized treatments. Soon, genetic diagnoses of infertility will be much more
accurate and reliable, especially for cases previously classified as
“idiopathic”. Couples will gain increased awareness of their reproductive risk,
even before attempting to conceive. Choice on possible alternative treatments
will be more informed. Women at risk of a premature decline of their fertility
due to genetic factors will learn about their condition and have the
opportunity to resort to fertility preservation solutions.
To fully unlock the potential of preconception genomics,
several critical steps must be taken. First, robust statistical methodologies
are needed to identify outlier cases in IVF for association studies. To date,
most studies have selected cases in an arbitrary and subjective manner, often
neglecting to account for the role of chance in poor IVF outcomes. Second,
large genomic datasets are essential for conducting agnostic association
studies and gene discovery, which will optimize the diagnostic yield for this
field. Finally, comprehensive biobanks, enriched with ancestry diversity, are crucial
for validating findings across different populations, ensuring the development
of equitable and generalizable testing programs.
Increased knowledge of developmental regulatory networks has
already the potential to re-tune the emphasis of reproductive studies from
observational to truly experimental, offering an opportunity for a paradigm
shift. Once in the spotlight of association studies, maternal genes products
suspected to govern pivotal oocyte and early embryo processes can be specifically
targeted to directly test their function. Indeed, harnessing recently developed
technologies, these products can be rapidly degraded within the oocyte
environment to assess the effects of their depletion.
In the longer term, novel avenues for treatment are
envisaged. In preclinical studies, injection of functional TRIP13 cRNA in MI
arrested oocytes obtained from a woman carrier of biallelic TRIP13 pathogenic
variants resulted in phenotypic rescue, with treated oocytes showing normal
subsequent maturation, fertilization and development to blastocyst stage.
Ideally, in the future, exogenous delivery of key maternal factors to oocytes
could be instrumental for groundbreaking achievements, such as to free
infertility treatment from the yoke of maternal age. The detrimental effect of
maternal age on embryo competence is largely caused by aneuploidies originating
during female meiosis. A major source of such meiotic errors is the progressive
depletion with age of specific proteins (e.g. shogushin 2) that normally assure
sister chromatid cohesion. Supplying fully grown prophase-arrested oocytes with
these proteins or their transcript could replenish the stock of cohesion
proteins and prevent or mitigate the age-depended increase in meiotic errors
occurring during the prophase-metaphase II transition.
Ultimately, revealing the genetics of early human
development will revolutionize the treatment of infertility, opening to the
full potential of precision medicine.
Source: Coticchio G, Cimadomo D, Capalbo A, Rienzi L, Early
embryo ontogeny and parental genetic legacy: from developmental mechanisms to
diagnosis and treatment, Fertility and Sterility (2024), doi:
https://doi.org/10.1016/j.fertnstert.2024.10.043.
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