However, vaccines’ advent, viral variants lurking on the horizon and other possible pandemic challenges make it necessary to maximize the experience gained through these difficult years. Antenatal management of pregnancies complicated by COVID-19 infection with severe respiratory failure is still heterogeneous and ethical concerns must be pointed out.To date, the impact of the COVID-19 pandemic on the world’s health, economics and politics is still heavy, and efforts to mitigate virus transmission have caused remarkable disruption. From the early onset of the pandemic, generated by SARS-CoV-2 spread, the scientific community was aware of its impact on vulnerable individuals, including pregnant women. The purpose of this paper is to highlight scientific pitfalls and ethical dilemmas emerging from management of severe respiratory distress in pregnant women in order to add evidence to this topic through an ethical debate. In the here-presented paper, three cases of severe respiratory syndrome are analyzed. No specific therapeutic protocol was available to guide physicians in a cost–benefit balance, and unequivocal conduct was not  The SARS-CoV-2 virus (acronym for Severe Acute Respiratory Syndrome Coronavirus) belongs to the Coronavirus family, pathogens responsible for both common infections of the respiratory system and for severe and life-threatening forms, such as MERS (Middle Respiratory Syndrome-Eastern) and SARS (Severe Acute Respiratory Syndrome) . CoronavNew mutant strains continue to appear, provoking public health shocks . Since iData on the effects during pregnancy of previous coronaviruses (severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS]) , along wInitially, a general tendency towards risk avoidance and lockdown masked some of the increased risks associated with SARS-CoV-2 infection in pregnancy ,11,12.Consequently, given the paucity of data, from the very beginning, there was a paramount effort from the scientific community to better understand the effects of SARS-CoV-2 infection on pregnancy, leading to fervent scientific activity ,14,15.Many studies have reported the prevalence of SARS-CoV-2 infection among pregnant women presenting to labor and delivery, with estimates ranging from 2–30% .Nevertheless, these rates are difficult to compare to other populations because universal screening is not commonly performed. This situation is different in the context of pregnant women.SARS-CoV-2 testing is often conducted as part of screening for hospital admission at delivery; however, pregnant and recently pregnant persons who test positive for SARS-CoV-2 infection are less likely to report symptoms .Pregnancy is associated with increased disease severity in those infected with SARS-CoV-2 .In parallel, maternal SARS-CoV-2 infection can impact pregnancy in numerous ways. The need for intensive care associated with severe disease can necessitate delivering the infant, causing an increased rate of preterm delivery. Placental infection can be associated with SARS-CoV-2 placentitis, which is related to an increased risk of stillbirth. Even in the absence of placental infection, inflammatory changes are observed in the decidua and placenta, and these may be linked to the increased risk of pre-eclampsia associated with SARS-CoV-2 infection in pregnancy. SARS-CoV-2 can also be vertically transmitted to infect the fetus, although this is uncommon .The National Institutes of Health (NIH) provides COVID-19 treatment guidelines for hospitalized adults. At the time of the study, NIH guidelines recommended dexamethasone or alternate systemic steroids and remdesivir to decrease severity among hospitalized patients who require supplemental oxygen or mechanical ventilation . There aThe COVID-19 Treatment Guidelines Panel recommends against withholding COVID-19 treatments from pregnant or lactating individuals specifically because of their condition .Normally, the therapeutic management of pregnant patients with COVID-19 should be the same as for nonpregnant patients, with a few exceptions (AIII). Notable exceptions include the recommendation against the use of molnupiravir for the treatment of COVID-19, unless there are no other options and therapy is clearly indicated .In fact, Remdesivir is the only antiviral drug that is approved by the Food and Drug Administration (FDA) for the treatment of COVID-19 but “the efficacy and safety profile of remdesivir among pregnant women with COVID-19 remain inconclusive. Even though better clinical status at baseline with earlier remdesivir treatment may result in better clinical outcomes, careful monitoring of adverse reactions and transaminase enzyme levels should be carefully monitored” .When other therapies are not available, pregnant people with COVID-19, which has a high risk of progressing to severe disease, may reasonably choose molnupiravir therapy after being fully informed of the risks, particularly if they are beyond the time of embryogenesis. In most cases, the timing of delivery should be dictated by obstetric indications, rather than maternal diagnosis of COVID-19. For people who had suspected or confirmed COVID-19 early in pregnancy and who recovered, no alteration to the usual timing of delivery is indicated  .The Society for Maternal-Fetal Medicine  supportsMany clinical trials evaluating novel treatments for COVID-19 have excluded pregnant persons; however, treatment recommended for the nonpregnant population should not be withheld from pregnant patients. This includes treatment with Remdesivir, dexamethasone and monoclonal antibodies. Given that pregnancy is a risk factor for progression to serious disease, pregnant persons are eligible to receive outpatient treatment or postexposure prophylaxis with antiSARS-CoV-2 monoclonal antibodies under the Emergency Use Authorization .Pregnant and breastfeeding women are excluded from participating in clinical trials during this pandemic . This “pThis is another missed opportunity to obtain pregnancy-specific safety and efficacy results, because therapeutics verified for men and non-pregnant women may not be generalizable to pregnant women due to their specific condition . PregnanIn our tertiary Italian Centre, almost 350 pregnant women with COVID-19 infection have been managed since March 2020. Here, we present three interesting cases.A 31-year-old Caucasian woman was admitted at the Emergency Department of University Hospital Federico II of Naples at 27 weeks of gestation, due to worsening of dyspnea.2, with length 165 centimeters (cm) and weight 70 kilograms (kg). Her pregnancy had been without complications.Her medical history was silent; she had neither comorbidities nor surgical history, except for the three CSs (Cesarean Section). The body mass index (BMI) on admission to the prenatal care Covid Unit was 25.9 kg/mShe reported a positive SARS-CoV-2 nasopharyngeal swab, which she performed after the onset of fever and loss of appetite. Two days after the diagnosis, due to the onset of dyspnea, she started a home therapy with deltacortene and amoxicillin–clavulanic acid.The woman was not vaccinated, nor were her whole family, most of whom resulted equally positive for SARS-CoV-2.2) of 82% on room air, respiratory rate of 40–50, blood pressure 110/70 mmHg, pulse 90 beats/minute and temperature 38 degrees Celsius (°C).At admission, she was febrile, with an oxygen saturation  showed a pH 7.4, pCO2 31.9, PaO2 72.4, HCO3–std 22.2, Base deficit −2.7 and O2 saturation 90%. Chest X-ray demonstrated diffuse bilateral consolidations; pulmonary ultrasound showed loss of normal echostructure of the parenchyma due to the presence of diffuse B lines; and a clinical exam revealed coarse and diminished breath sounds. Obstetric examination including an abdominal ultrasound showed no abnormalities.The patient was given dexamethasone 6 mg, paracetamol for pain and fever relief and ceftriaxone 2 g; she also received thromboprophylaxis with enoxaparin 4000 units/day subcutaneously. Her SpOFor two days, the patient’s clinical condition was closely monitored and seemed relatively stable. Antenatal corticosteroids prophylaxis was carried out with two doses of 12 mg betamethasone every 24 h. Despite ongoing antibiotic therapy, the patient had an increase in white blood cells (18.520/uL) and PCR (107.10 mg/L), then ceftriaxone was discontinued and meropenem and azithromycin were added to the therapy.Three days after the hospitalization, the patient had a drastic worsening of respiratory function; she was agitated and not cooperating.Several C-PAP attempts had been unsuccessfully made due to the lack of compliance of the patient to the Boussignac mask and to the Helmet. Because of the persistent worsening of the patient’s clinical and respiratory condition, the woman was intubated and transferred to the Intensive Care Unit. Her obstetric condition was stable. A combined evaluation between obstetric anesthesiologists and neonatologists before intubation had been necessary, and an appropriated counselling had been carried out to the mother.Due to the critical clinical condition of the patient, a fetal neuroprotection therapy with Magnesium Sulfate was given.In the Intensive Care Unit, the patient underwent daily hematochemical analyses and ABG. Several adjustments in the ventilation mode had been made to ensure the best oxygenation.Her condition deteriorated on day 7 of the admission.Gynecologists and virologists were immediately alerted to decide on the management of the patient. Despite her worsening condition, the fetal situation was stable and normal intermittent US controls were recorded. Since the general condition of the patient had worsened, a decision was made to deliver by CS , on maternal indication.A male baby was delivered, with birth weight 1200 g, birth length 37 cm and head circumference 24.5 cm. The cord was clamped immediately after birth. The Apgar score was 5 and 7 at 1′ and 5′, respectively.Nasopharyngeal swabs for SARS-CoV-2 detection were collected at 48 and 96 h of life and were found to be negative in both instances.The baby is still alive, but in severe clinical condition due to severe prematurity.A 31-year-old Caucasian woman was at 27 weeks of gestation. Due to the onset of dyspnea, a SARS-CoV-2 nasopharyngeal swab was performed and it resulted positive. The patient was transferred to the nearest local COVID Center. The woman was not vaccinated against SARS-CoV-2.2) of 87% on room air and a respiratory rate of 35–45, blood pressure 100/65 mmHg, pulse 85 beats/min and temperature 39.3 degrees Celsius (°C). The patient was given dexamethasone 4 mg (twice a day), paracetamol for fever and pain relief and amoxicillin—clavulanic acid 1 g (three times a day). She also received thromboprophylaxis with Enoxaparin 4000 units/day subcutaneously. Obstetric examination including an abdominal ultrasound showed no abnormalities.At the time of admission, she was febrile with an oxygen saturation . The clinical exam revealed coarse and diminished breath sounds. 2O, FiO2 60%). Her ABG showed a pH 7.42, pCO2 31, PaO2 55, HCO3–std 22.0, Base deficit −4.4 and O2 saturation 89%. For critical clinical and instrumental conditions, it was decided to start NIV with Helmet  was requested.After 24 h in NIV, a worsening of respiratory function was manifested by clinically evident fatigue. After mild sedation, orotracheal intubation was performed. On the second day of hospitalization, the patient was transferred to the prenatal care Covid Unit of Federico II University Hospital in Naples in severe ventilatory condition, despite orotracheal intubation. The fetal situation was stable and US controls were recorded. Since the general condition of the patient had worsened, a decision was made to deliver by CS , on maternal indication. Prior to CS, only one dose of betamethasone 12 mg was taken for antenatal corticosteroids prophylaxis. The patient died due to multiorgan failure almost two months after delivery.At 48 h after CS, the patient had fever (38–40 °C) and tachycardia (120 bpm). The respiratory conditions remained extremely serious. On the sixth day of hospitalization, serum galactomannan and coproculture for Clostridium Difficile serum tested positive. From the respiratory point of view, the patient’s condition had been stationary, but serious for weeks. The mechanical ventilation mode (IPPV) was never changed and a total of seven pronation cycles were carried out. The newborn died due to severe prematurity after 19 days.A woman pregnant at 26 gestational weeks referred to Federico II University Hospital in Naples for fever, cough and dyspnea. She was carrying a dichorionic diamniotic (DCDA) twin pregnancy complicated by gestational diabetes, with healthy fetuses. She was not vaccinated against SARS-CoV-2.She tested positive for the Covid infection. After two days, she was transferred to the Infectious Diseases Department. Diagnostic imaging revealed widespread bilateral interstitial pneumonia, complicated by gross inflammatory thickening in the left mid-basal site . During hospitalization, the patient had a rapid worsening of clinical conditions with a desaturation, despite high-flow oxygen therapy, for which it was decided to transfer to intensive care.She underwent non-invasive ventilation with a helmet. Despite the established therapy, the patient was tachypneic and maladapted, with evident muscle fatigue, for which she was intubated, and subjected to mechanical ventilation. The patient was given Enoxaparin 4000 UI twice a day, dexamethasone 12 mg, paracetamol, iron and folic supplementation, Cefepime 2 g twice a day, Azithromycin 500 mg, Clindamycin 600 mg, Meropenem 2 g, Fluconazole 200 mg, casirivimab, and imdevimab monoclonal antibodies, KCL retard 600 mg, N-acetylcysteine mucolytic 300 mg. 2, 80.8, PaO2 28.3, HCO3–std 31.5, HCO3–act: 37.8, Base excess 8.8 and O2 saturation 47.5%, Hct: 3.6, glycemia: 123 mg mg/dL, Hb 10.9, Calcium: 4.6 mg/dL, Cl: 92 mmol/L, Na: 135 mmol/L and K: 3.29 mmol/L.From repeated obstetrical ultrasound checks, the pregnancy resulted in normal evolution. The patient’s precarious conditions with continuous phenomena of desaturation made urgent a CS at 27 weeks of gestation, performed after fetal neuroprophylaxis with magnesium sulfate. Her last ABG showed: pH 7.28, pCOIn the following days, the patient’s clinical situation continued to worsen, with diffuse pneumothorax to the right, flap and pneumomediastinum. Such a framework would lead to cardiorespiratory failure and the patient’s death a month after the cesarean section.Newborns (a boy and a girl) were transferred to the Neonatal Intensive Care Unit. At birth, their Apgar scores were 4-7-7 for him and 1-5-7 for her at 1′, 5′, and 10′, respectively. The newborns’ birth weight was 960 g for the male and 730 g for the female. Positivity to SARS-CoV-2 was ascertained for both of them. They suffered from necrotizing enterocolitis and were transferred to a tertiary care center and then discharged home after the appropriate treatments and the attention given in case of prematurity.In these cases, what seems to be clear was the absence of a definite obstetric therapeutic protocol. Patients were managed with a multidisciplinary approach. The fetal situation was stable. All efforts converged to save the mother by actuating all different therapeutic options, including pronation, but the maternal survival rate was already compromised. All cases converge to the result that the best clinical treatment under specific circumstances was given.Through this pandemic period, that cannot be considered to be over yet, at least three serious issues were raised in this peculiar care setting. Firstly, considering the possibility of intubation and transfer to the Intensive Care Unit, should the patients receive counselling for termination of pregnancy (TOP) or is it better to “wait and see”? 2 at 70 mmHg, with oxygen saturation between 94% and 98% [This apparently pointless consideration came from the lack of evidence regarding possible effects of prenatal exposure to high doses of oxygen during fetal life, or to some drugs, especially in the second trimester of pregnancy . In fact and 98% .p < 0.001, by a log-rank test) [From an infectious disease perspective, delivery can give the patient the chance to be treated with antivirals, of which the safety in pregnancy is uncertain. An example of this therapy is Remdesivir. It is an antiviral drug approved for COVID-19 treatment in the early stages of the pandemic, but data on pregnancy are incomplete ,32. Despnk test) . To datenk test) .Literature is still poor in cases of use of some other antiviral drugs, such as tocilizumab, or monoclonal antibodies in pregnant women, despite significative results in terms of severe morbidity . The timing and the mode of delivery are to be chosen considering gestational age and maternal symptoms; no clear data are available in case of critical maternal condition during the different gestational periods ). AccordSecondarily, it is not known whether a TOP, as last therapeutic chance, could improve maternal outcome and change the natural history of the disease when maternal COVID-19 is severe . TOP migThirdly, what is the best method of induction in the case of TOP? In this case, there is no evidence to state a traditional protocol that could not worsen maternal conditions. Considering that prostaglandins are contraindicated in the case of severe asthma, mechanical methods could be preferred in these patients. If at the very beginning of pandemics, with the unknown effect on pregnancies and the lack of therapeutic safe treatments, the biggest dilemma was how to treat a pregnant woman affected by COVID-19, with the advent of vaccines the dilemma has shifted to the healthy pregnant . In bothData on vaccine coverage suggest that pregnant women are less likely to receive a COVID-19 vaccine, despite their increased risk for severe disease and the risks of adverse pregnancy and neonatal outcomes if infected. A percentage coverage of 71%  suggestsMore recent meta-analysis of 111 studies, which compared outcomes for pregnant patients infected with SARS-CoV-2 with those who were not infected, found that infection significantly increased the odds of premature delivery , pre-eclampsia , stillbirth , neonatal mortality  and maternal mortality  .In Scotland, 68% of the pregnant population was unvaccinated by October 2021, but unvaccinated individuals accounted for 77.4% of all SARS-CoV-2 infections, 90.9% of COVID-19 hospitalizations and 98% of intensive care unit admissions among pregnant people; furthermore, all perinatal deaths following SARS-CoV-2 infection in pregnancy occurred in unvaccinated individuals .Most experts believe that SARS-CoV-2 is likely to become endemic. Thus, the continued collection of data on the effects of SARS-CoV-2 infection during pregnancy and the effects of COVID-19 vaccines are needed .In the presented cases, a multidisciplinary approach based on informed consent  could haThere is a need for evidence about pregnancies complicated by COVID-19 with severe respiratory complications.More studies could be helpful in order to answer a new ethical dilemma: can TOP be considered as an option  in case Apart from a specific dilemma, one fundamental instrument should be taken into account as being the milestone of the care relationship: informed consent.It is the legitimation of the medical act. A truly informed consent is based on adequate information and is the trademark of cooperation between doctor and patient, a real therapeutic alliance .It was clear during these years that the scientific world did not have immediate knowledge about COVID-19 pathogenesis, risk of maternal infection and treatment during pregnancy. Considering these limitations, all care workers made a great effort to treat population, with special regards to vulnerable individuals .Dilemma is always a matter of value. Even in the complete darkness of a new situation to confront with, only a real informed consent guarantees medical doctors and health professionals, in general, a correct way to act and to avoid future malpractice claims .Given the increasing connectedness of the world’s population, climate change, and the increasing encroachment of human populations on wildlife habitats, the emergence of another infection with global effects is likely. Knowledge derived from the COVID-19 pandemic can be fruitful in response to emerging infections in the future ,50.In conclusion, a patient-centered multidisciplinary approach made it possible to overcome pandemic challenges and seems to be crucial in relation to future scenarios.


As the third generation of new thin-film solar cells, perovskite solar cells (PSCs) have attracted much attention for their excellent photovoltaic performance. Today, PSCs have reported the highest photovoltaic conversion efficiency (PCE) of 25.5%, which is an encouraging value, very close to the highest PCE of the most widely used silicon-based solar cells. However, scholars have found that PSCs have problems of being easily decomposed under ultraviolet (UV) light, poor stability, energy level mismatch and severe hysteresis, which greatly limit their industrialization. As unique materials, quantum dots (QDs) have many excellent properties and have been widely used in PSCs to address the issues mentioned above. In this article, we describe the application of various QDs as additives in different layers of PSCs, as luminescent down-shifting materials, and directly as electron transport layers (ETL), light-absorbing layers and hole transport layers (HTL). The addition of QDs optimizes the energy level arrangement within the device, expands the range of light utilization, passivates defects on the surface of the perovskite film and promotes electron and hole transport, resulting in significant improvements in both PCE and stability. We summarize in detail the role of QDs in PSCs, analyze the perspective and associated issues of QDs in PSCs, and finally offer our insights into the future direction of development. With the growing world population and the rapid development of industrial civilization, fossil fuels such as coal, oil and natural gas are being used in large quantities . Thus, t2, SnO2, phenyl-C61-butyric acid methyl ester (PCBM). The HTL is generally 2,2′,7,7′-tetrakis--9,9′-spirobifluorene (Spiro-OMeTAD), polytriarylamine (PTAA), NiO, poly(4-butylphenyldiphenylamine),poly polystyrene sulfonate (PEDOT:PSS). Recently, PSCs have registered a maximum efficiency of 25.5% [Among the many solar cells available, perovskite solar cells (PSCs) stand out for their excellent photovoltaic properties. PSCs usually consist of the electron transport layer (ETL), the light-absorbing layer and the hole transport layer (HTL) ,6. The EHowever, compared to silicon-based solar cells, the stability of PSCs in the environment is poor ,9. ThereAlthough the application of QDs in PSCs has been reported, the collated data lack comprehensive classification and summary. In this article, we analyze, in detail, QDs as additives in electron transport layers (ETLs), hole transport layers (HTLs) and perovskite films, and directly as electron transport materials (ETMs), hole transport materials (HTMs), light-absorbing layers and luminescent downshifting materials. More importantly, we summarize the role of QDs in PSCs and analyze the perspectives and associated issues. Finally, future research directions are proposed for the application of QDs in PSCs.QDs are semiconductors, considered QD materials with their volumetric footprint strictly restricted at the nanoscale, and are mostly prepared by thermal injection and low-temperature solution methods. They have shown great application in solar cells ,17, photScholars applied QDs in PSCs and found that QDs can optimize the energy level arrangement, enhancing charge transport . They ca(1)Proper alignment of energy levels to allow for the efficient extraction of electrons.(2)High electron mobility to transfer the photogenerated electrons to the external circuits faster. However, electron transport and extraction in the ETL of PSCs are not ideal, showing stability and hysteresis issues. QDs doping into ETL presented an effective method for optimizing ETM. The electron transport layer (ETL) has the function of collecting and transporting electrons to the conductive glass, while effectively blocking holes from recombination. The ideal electron transport material (ETM) should have the following properties: 2, SnO2 and PCBM in order to improve the performance of PSCs and increase PCE.Carbon is a popular building material due to its low price, high surface area and abundant resources . Doping 2 has a suitable energy band structure and excellent chemical properties, generally considered the material of choice for mesoporous scaffolds and compact layers for PSCs. On the other hand, TiO2 has the disadvantages of low electron mobility (~10−4 cm2 V−1 s−1) and low conductivity (~1.1 × 10−5 S cm−1). Under UV light, it has strong photocatalytic effects that can easily cause the decomposition of perovskite. To solve the problem of slower charge transfer, Li et al. [2 as ETL for PSCs in 2017, showing that CQDs can enhance electron extraction and electron coupling between the perovskite and ETL, also achieving better energy level matching (2 (m-TiO2) layer in PSCs using the modified hydrothermal method to prevent the UV-induced decomposition of perovskite films. CQDs effectively converted UV light into blue light and significantly enhanced the light stability of PSCs. In total, 70% of the initial efficiency was maintained after 12 h of full sunlight, much higher than the 20% initial efficiency of the bare device. Finally, the PCE had improved by 16.4%. In 2019, Zhu et al. [− ions from undergoing interfacial diffusion and inhibited the decomposition of perovskite , and compounded them with SnO2. The g-C3N4 QDs can recast the electron density distribution of SnO2 crystal units, thereby eliminating the oxygen vacancy reduction trap center and facilitating electron transport. The final equipment manufactured achieved a PCE of 22.13%. The device still had an initial PCE of 90% after aging at relative humidity (RH) of 60% for 1500 h, which is undoubtedly an important step for PSCs.Furthermore, in 2020, Hui et al.  preparedn et al.  designedBy introducing CQDs into the ETL, not only can the extraction rate of electrons be increased, but also the long-term stability of PSCs can be improved. The test results showed that PSCs were still effectively improved under the harsh conditions ,27,28,29GQDs are composed of single- or multi-layer graphene. Compared to graphene nanosheets with zero band gap and a low light-absorption coefficient, GQDs have some special photovoltaic properties. Examples include ultra-fast electron extraction rates (time constants of less than 15 fs), extremely long hot electron lifetimes (up to hundreds of picoseconds), broad light absorption and fluorescence properties .2-based cells had the highest PCE of 14.36%. In 2018, Shen et al. [2. GQDs can effectively penetrate and cover the pores and cracks of the m-TiO2 film, making the modified TiO2 smoother. This resulted in better contact with the perovskite film, reduced the resistance inside the equipment and enhanced the charge transfer between perovskite and ETL. It was eventually found that a PCE of 20.45% could be achieved based on GQDs of size less than 5 nm. Xie et al. [2 film. The photogenerated electrons in GQDs can be transferred to the conduction band of SnO2, enhancing the conductivity of SnO2, improving the electron extraction rate and reducing the complexation of the perovskite interface with ETL. The work function in light conditions dropped form 4.6 eV to 0.25 eV. The maximum steady state PCE was 20.23% and the cell had a small hysteresis.In 2019, Ebrahimi et al.  synthesin et al.  synthesie et al.  reduced 2 nanoparticle composites (G@SnO2). Compared to pure SnO2, G@SnO2 formed high-quality films and better energy level alignment on the basis of an ETL with a higher transmission rate, and then found that GQDs had the best PCE of 19.6%. In addition, the device bent at a radius of 7 nm maintained 91% of the initial PCE after 500 bending rounds  reached 1.17 V, and the stability greatly improved. The device retained 80% of its initial performance after 56 days in the environment with an RH of 30%~40%. This modification is simple to perform and provides a simple method for preparing PSCs close to the theoretical PCE.In the same year, Nagaraj et al.  used GQDs on ETL d,e. Aftesc) and Voc were greatly improved . In addition, 1% CdS QDs allowed the simultaneous optimization of the perovskite film and the SnO2 layer, regulating the energy level matching between the two layers and accelerating the charge transport. Not only that, but S2− ions in CdS QDs will form strong coordination bonds with Pb2+ ions in the perovskite, establishing micro-channels that likewise speed up the charge extraction between perovskite and ETL. The final result was that the CdS (1%)-SnO2 based device achieved a PCE of 20.78% and the stability in air was good.In 2021, Lv et al.  reported2 and the light-absorbing layer to prepare planar-structured PSCs. The two-layer optimization strategy achieved the desired results, with passivation of SnO2 surface defects and an increase in conductivity in the dark case. Then they used 3-aminopropyltriethoxysilane (APTES) to surface-modify BP QDs by doping them into the light-absorbing layer. As a result of the improved grain boundaries, Voc increased directly to 1.22 V. The energy band structure had also been significantly optimized (2 to prepare fluorine-doped tin oxide-coated (FTO)/SnO2:BP QDs/perovskite/Spiro-OMeTAD/Ag-structured PSCs. The doping of BP QDs not only had a beneficial effect on SnO2 by passivating its defects, but also inhibited the oxidation of the BP QDs themselves. This certainly adds to the competitiveness of BP QDs among many QDs.On the other hand, in 2021, Zhang et al.  broke wiptimized c. The fi2 is generally used as the ETL for PSCs, with fewer reports on SnO2 QDs modifying PSCs. In 2022, Zhou et al. [2 QDs with m-TiO2 as the ETL  into perovskite precursor solutions is a viable and effective strategy. In 2017, Zou et al.  added CQo et al.  similarl2+ ions to form the adduct CQDs-PbI2, which as a hetero phase nucleation site for MAPbI3, making the surface defects of the film passivated  have also been added to perovskite films to improve the quality of films and enhance the photovoltaic performance of devices. In 2020, Gong et al.  reportede device e, and th3−x and PbS QDs hybrid precursors. The one-step strategy was simpler than the two-step strategy and retained the photovoltaic properties of the perovskite and QDs. XRD showed that the addition of too many PbS QDs can have a bad effect on perovskite crystallization. Moderate amounts of PbS QDs can promote perovskite nucleation and reduce surface defects. The band edge shifted due to the narrow band gap of the PbS QDs and the small strain at the MAPbI3-PbS interface, enabling the film to have an enhanced light absorption range. The PCE of the final device was 18.6%. In 2019, Ngo et al. [2/FAPbI-PbS/Spiro-OMeTAD/Au device was 18.00%. The next year, Zhang et al. [In current research, metal sulfide QDs have been widely used in PSCs, particularly PbS QDs, which can absorb light in the infrared range. In 2018, Han et al.  creativeo et al.  tested to et al.  embeddedg et al.  introduc2 QDs as additives to perovskite film by pulsed laser irradiation in the green anti-solvent ethyl acetate (EA); the process is shown in 2 QDs was the optimum concentration. When the concentration was too high, the WS2 QDs became the center of new trap state, increasing the trap density on the surface of the film and discouraging the charge transfer. The final maximum PCE was 16.85%.In 2021, Li et al.  prepared3 inverse opal (IO) in 2019  crystal plane content and crystallinity of the film. In addition, because of the low band gap of SnS QDs (1.3 eV), the hybrid film enhanced the light capture in the visible and near-infrared light range (wavelength 800–900 nm), as well as the incident photocurrent conversion efficiency (IPCE) spectra. In 2022, Ou et al. [2AgBiBr6 by the non-aqueous solvothermal method. The (111) crystal plane spacing of SnS QDs was 0.284 nm, while the (400) crystal plane spacing of Cs2AgBiBr6 was 0.287 nm, which was a good match between them. The introduction of SnS QDs provided nucleation sites for the formation of film and improved the crystallinity of perovskite while reducing the density of defects. The PCE of the final non-toxic PSC obtained was 1.95%, despite the low efficiency, which was the beginning of an emerging future for non-toxic calcium titanite solar cells.S and Sn are abundant resources and environmentally friendly, so they are being exploited by researchers. Han et al.  embeddedu et al.  added no2+/Sn4+ oxidation, making PSCs less stable and low PCE. There are many ways to inhibit the oxidation of Sn2+/Sn4+ ions, but all of them contain additives, which can introduce impurities, directly reducing the performance of PSCs. Thus, in 2021, Mahmoudi et al. [2+/Sn4+ ions, and no impurities were introduced , impeding the growth of the perovskite nuclei and increasing their crystallinity. Moreover, defects can be passivated by QDs, resulting in lower residual tensile strain in the film. In addition, compared to the conduction band (CB) of the perovskite with −4.10 eV, the CB of the modified perovskite with Ti3C2Clx QDs (−4.23 eV) was closer to the CB of the SnO2 (−4.31 eV), demonstrating that a better energy level alignment had been formed between the perovskite and ETL. Because of the accelerated charge transfer, the final PCE of the device was 21.31%, which was an encouraging value.Tiu et al.  fabricat melting e. This mThe hole transport layer (HTL) in PSCs serves to extract, collect and transport the holes generated by the light-absorbing layer to the metal electrode and to block the injection of electrons. It has a key influence on the photovoltaic performance and stability of PSCs. Therefore, it should have excellent cavity transport. The highest occupied molecular orbital (HOMO) energy level of the ideal HTL should be compatible with perovskite’s valence band edge energy level to minimize energy barriers. Currently, Spiro-OMeTAD is the most widely used HTM, but it is highly hygroscopic and tends to cause damage to perovskite films, and the energy-level mismatch with the active layer of the perovskite leads to a high loss of energy during transport . It is iIn 2021, Liu et al.  synthesiAfter Spiro-OMeTAD was first used as HTM, NiO was also gradually widely used as the HTM for inverted PSCs due to its solution processability and high light transmission. However, there is also an energy level mismatch and low electrical conductivity of NiO. To settle these issues, in 2020, Kim et al.  prepared3 PSCs. As a result of the aforementioned HTL bilayer characteristics, faster hole extraction, superior quality MAPbI3 crystals, and better interfacial morphologies were achieved. Finally, they obtained a PCE of 17.2%. In 2020, Kim et al. [O9.67% was employed with Spiro-OMeTAD, where crystallization was effectively retarded, it can enhance the stability of the PSC. Notably, the devices with rGO in Spiro-OMeTAD demonstrated more stable performance at 85 °C, showing an ~30% PCE drop over 62 h compared to 51% for the device without rGO.GQDs are also widely doped into HTL by researchers . In 2017m et al.  systematIn 2020, Wang et al.  modified2 on PEDOT:PSS/GQDs film  and high leakage current in HTL, Li et al.  preparedQDs film d, and th2 and sp hybridization, and thus it has a graphene-like structure. In 2015, Xiao et al. [2–sp hybrid graphdiyne has potential applications in the field of optoelectronics.In addition, graphdiyne quantum dots (GD QDs) are potential materials that can be doped into HTL. Graphdiyne is a Π-conjugated material with spo et al.  first do4(PbO)4 QDs into Spiro-OMeTAD. Not only was its conductivity increased, but also the stability of conductivity was enhanced. Similar to the effects of other QDs, PbSO4(PbO)4 QDs enhanced the ability to extract holes from perovskite to HTL. The final PCE for the device was 22.66%. The introduction of PbSO4(PbO)4 QDs filled the blank in multi-element QDs’ doping of HTL, which is a milestone at present when only single-element QDs are generally used as additives in the HTL.In 2022, Zheng et al.  first doQDs can also be used directly as electron transport material (ETM), hole transport material (HTM) and light-absorbing layers, in addition to being used as additives and interfacial modifications. Metal oxide QDs are used by researchers as ETM for PSCs now, offering superior properties compared to current metal oxide materials. In 2015, Ameen et al.  used ZnO2, TiCl4, TAA (titanium diisopropoxide bis(acetylacetonate)) by spin coating. Among them, the TiO2 QDs performed well, as their low series resistance and high parallel resistance resulted in faster charge transfer and a final PCE of 16.97%, much higher than the PSCs based on TiCl4 and TAA . Nb5+ doping increased the conductance through the np-TiO2 ETL, reduced the series resistance and improved the performance of the PSCs. The optimal PCE they obtained was 19.5%.In 2015, Tu et al.  prepared and TAA a. In 2012 QDs -SnO2) at the bottom and potassium-capped SnO2 nanoparticle layers (NP-SnO2) at the top enhanced the charge transport properties of PSCs, and significantly reduced the degree of ion migration. The resulting optimal PCE reached 20.4%, and strongly reduced J-V hysteresis for PSCs. This research provided a good example for optimizing bilayer ETLs in the future.The annealing process is the most important step in the fabrication of SnOg method  and the g method . Althougg method  first usf 17.66% d. The mePCBM is a tradition class of highly conductive material, but it is too costly to be used on a large scale. In 2017, Tan et al.  used pyrCompared to bulk materials, QDs have a tunable band gap and they are able to optimize energy level arrangements. Therefore, QDs have great potential for applications as ETM.Among the current hole transport materials (HTMs), Spiro-OMeTAD and PEDOT:PSS are the two most widely used. However, when Spiro-OMeTAD is used as the HTM, additives have to be added. The use of additives increases the manufacturing costs and makes Spiro-OMeTAD hydrophilic. PEDOT:PSS is inherently hydrophilic and is highly susceptible to absorb atmospheric moisture to reduce the stability of PSCs, in addition to its high acidity, which tends to corrode ITO. Therefore, the search for new HTMs is urgent. QDs have been adopted as an HTM in PSCs because of their high hole transport rate and their ability to optimize energy level alignment. In 2015, Hu et al.  used PbS2 surface, this resulted in a device with only 3% PCE at that time. In another study, the HTM with high cost and a complex structure was substituted with CQDs by Kasi Matta et al. [In 2016, Paulo et al.  used a pa et al. . Good ho2 QDs had an improved hole extraction capacity, with a final PCE of 12.80%. When they used Spiro–OMeTAD as the HTM, the device had the highest Voc and Jsc and a PCE of 15.6%. There is still a gap between CuInSe2 QDs and Spiro-OMeTAD, but CuInSe2 QDs as an HTM can improve the stability of the PSC . Wu et al. [2ZnSnS4 QDs as an HTM, and the device showed significantly optimized light absorption in the visible region from 400 to 800 nm, ultimately resulting in a PCE of 12.75%. In 2016, Yuan et al. [2ZnSnS4 QDs into PSCs, and then replaced the S atoms with Se atoms to obtain a better energy band alignment. However, due to the relatively shallow valence band of Cu2ZnSnS4 QD devices, there was a decrease in PCE from 10.72% to 9.72%. In 2019, Zhou et al. [3 PSCs after using Cu2ZnSnS4 QDs as the HTM, with significant higher extraction and hole transport rates.The quaternary semiconductor Cuu et al.  used Cu2n et al.  introducu et al.  obtained2O-based PSCs are generally inverted structures, while few PSCs have been reported for n-i-p-type structures. In 2019, Liu et al. [2O QDs as HTM for n-i-p-type PSCs. They modified the surface of Cu2O QDs with ethenyltriethyloxysilane, introduced hydrophobic groups to improve the hydrophobicity of PSCs, and eventually obtained a PCE of 18.90%, which was the highest efficiency for Cu2O-based PSCs at that time.Cuu et al.  used Cu2Compared to conventional HTMs, the PCE of PSC-based QDs as HTMs is significantly lower, which is the shortcoming of QDs as an HTM. However, on the basis of stability, QDs are superior to conventional HTMs. In terms of future PCE improvements, there is a huge upside for QDs.Perovskite quantum dots (PQDs) have been fabricated by researchers as light-absorbing layers due to their high photoluminescence quantum yield (PLQY) and tunable forbidden bands, which are beneficial for enhancing the light capture capability of the devices. 3 QDs. In 2017, Sanehira et al. [3 QDs together, with the structure shown in 3 QDs facilitated the extraction of holes, and the final device showed an extremely low Voc loss of just 0.42 eV, the lowest loss ever recorded at that moment. The final PCE was 12.55%. To further optimize the films of PQDs and improve the performance of the device, in 2019, Shi et al. [3 quantum dot (Yb-CsPbI3 QD) films  films b, and th+ ions to Cs+ ions and improved the electron and hole transport rates, ultimately achieving a PCE of 16.60% with a Cs0.5FA0.5PbI3 QD-based device. Li et al. [3 QDs with wide bandgap CsPbI3 QDs to form a gradient heterojunction. By the proportional modulation of the hybrid QDs, a suitable energy band alignment was obtained, facilitating charge coupling, and the final PCE was 15.6%. In addition, the environmental stability was improved, as shown in The mixing ratio of ions also plays a significant role in the films’ PQDs, and ion engineering plays a key role in optimizing the QD films. Hao et al.  reduced i et al.  mixed naPQDs generally require ligand exchange and the long-chain groups on their surfaces, which are not conducive to charge transport in the device. In 2019, Ling et al.  used sho1−xPbxI3 QDs by mixing CsPbI3 QDs with CsSnI3 QDs. The hybrid QDs maintained a stable phase for several months and increased the speed of photogenerated electron transport with a final PCE of 0.1%. Following this, Wang et al. [3 QDs via a single pot. Due to the addition of triphenyl phosphite (TPPi), the oxidation resistance of the PSC was substantially improved, maintaining a stable phase at room temperature for more than 90 days, and the PCE of the optimal device reached 5.03%. The addition of antioxidants made the CsSnI3 QDs films more stable and provided a simple method for producing highly stable lead-free inorganic PQDs, giving great potential for the widespread use of lead-free inorganic PSCs.Sn-based PQDs have also been investigated. In 2017, Liu et al.  preparedg et al.  synthesiThe PCE of quantum dot perovskite solar cells is currently improving, and has already increased to over 15% e. In the2, which can significantly reduce the stability of PSCs. Therefore, the use of UV and IR light can not only improve the PCE, but also the stability of the device. Currently, most PSCs can only use visible light in the 400–800 nm range, which is only about half of the solar radiation. Light in the under-ultraviolet (UV) and infrared (IR) regions cannot be absorbed by PSCs, resulting in an invisible waste of energy, so more and more researchers are looking to capture light in the UV and IR regions to make the most of it. In addition, UV light tends to cause the catalytic decomposition of materials such as TiO3 QDs on the transparent side of PSCs for the first time (3:Mn luminescent down-shifting (LDS) film automatically degraded under moist heat or high temperature, which was detrimental to the stability. This work broke away from the traditional thinking of optimizing devices and opened up a new avenue for device optimization. In another study, Wang et al. [sc were found to be 20.3 mA cm−2 and PCE was 17.3%. Respectively, when the QD concentration was 0.2 mg/L, in 2019, Bian et al. [3:Mn QDs, N-GQDs have stable chemical bonds and still work stably under humid and hot environments  resulted in a device with improved Jsc and FF compared to CQDs embedded in PMMA (CQDs@PMMA) films  films d. This wIn another study, Anizelli et al.  reportedThe phototransfer layer effectively converts UV to visible light, improving PCE and stability. The photoluminescent materials are able to monitor the performance of PSCs and add a pathway for QDs to optimize PSCs.Although the introduction of QDs can increase the performance and stability of PSCs by a substantial margin, there are some problems with QDs that prevent them from unlocking their full potential, and some aspects need to be improved.First of all, the manufacturing method of QDs is a key step. The predominant fabrication methods are currently thermal injection and low-temperature solution. Not only are these methods required to introduce the ligands, but also require high temperatures for thermal injection, which can have a negative effect on the perovskite film and increase the manufacturing costs. Therefore, it is extremely important to help to develop new methods of preparation. In this paper, many excellent methods are mentioned, such as microwave synthesis for the uniform heating of QDs, thus controlling the crystallization rate. The supersaturated recrystallisation method allows the preparation of QDs with a high degree of stability. In addition, pulsed laser radiation is the latest method for the preparation of QDs, which is rapid. Most importantly, the crystallization of the film is not affected by the introduction of ligands during the preparation process. These methods have great potential for optimizing QDs and increasing yields.2+ ions are considered to be an effective alternative to the toxic Pb2+ ions in perovskite. Future research on Sn-based PSCs should be increased.Secondly, the element doping of QDs is also an effective tactic to increase the PCE. Element doping can improve the rate of charge transport, but not all element doping will improve the performance of PSCs. Some ions do not match the lattice of perovskite, which will lead to a reduction in device performance. For this reason, we need to find matching QDs for the study of this approach. SnThirdly, ligand engineering is also an effective method for modifying QDs. Ligands can be divided into two types: long-chain ligands and short-chain ligands. Perovskite QDs are generally stabilized by long-chain insulating ligands, but the long-chain ligands inhibit charge transport. Short-chain ligands, although beneficial for charge transport, can cause the agglomeration of QDs. It is necessary to find suitable ligands to exchange with the oleic acid ligands on the surface of the perovskite to improve the conductivity, while maintaining the black stable phase of the perovskite. There have been attempts by researchers to prepare ligand-free perovskite with high charge transport, but with a PCE below 10%. This method is also a promising strategy.Fourthly, the choice of solvent is also important in the production of QDs. Highly polar solvents break the ionic bonds formed between the long-chain ligands and the perovskite surface, while highly non-polar solvents are unable to remove the long-chain ligands, and the QDs will agglomerate. Therefore, the use of solvents with medium polarity is an effective route. Most of the moderately polar solvents used today are low-toxicity green solvents, such as ethyl acetate and methyl acetate, which can remove long-chain ligands while maintaining the stability of QDs.3-based PSCs. The toxic PbI2 can be recycled, and after recrystallization, can be employed to prepare the device, with a PCE reaching 13.5%. In addition, they were able to recycle the expensive FTO/glass substrates several times. In 2017, Xu et al. [2 from thermal decomposition CH3NH3PbI3 perovskite films for efficient PSCs. This approach can reduce the risk of Pb outflow. In 2022, Hong et al. [18Mg2(HPO4)2(PO4)12), which can act as a high-performance Pb2+ absorbent. Their method provided an efficient way to remove Pb2+ ions from water and recycle the PSCs. We should explore more novel approaches to recycling the Pb in PSCs, as this will bring us one step closer to commercialization.Fifthly, since many PSCs contain toxic Pb, a sustainable procedure to recycle the cells after their operational lifetime is required to prevent the exposure of Pb to the environment. In 2016, Binek et al.  demonstru et al.  developeg et al.  investigAll of these approaches can be used to optimize the performance of QDs and strengthen the performance of the PSCs. We are confident that QDs will make a big difference in the field of PSCs.


The importance of right heart failure (RHF) treatment is magnified over the years due to the increased risk of mortality. Additionally, the multifactorial origin and pathophysiological mechanisms of RHF render this clinical condition and the choices for appropriate therapeutic target strategies remain to be complex. The recent change in the United Network for Organ Sharing (UNOS) allocation criteria of heart transplant may have impacted for the number of left ventricular assist devices (LVADs), but LVADs still have been widely used to treat advanced heart failure, and 4.1 to 7.4% of LVAD patients require a right ventricular assist device (RVAD). In addition, patients admitted with primary left ventricular failure often need right ventricular support. Thus, there is unmet need for temporary or long-term support RVAD implantation exists. In RHF treatment with mechanical circulatory support (MCS) devices, the timing of the intervention and prediction of duration of the support play a major role in successful treatment and outcomes. In this review, we attempt to describe the prevalence and pathophysiological mechanisms of RHF origin, and provide an overview of existing treatment options, strategy and device choices for MCS treatment for RHF. The number of heart failure (HF) patients reached more than 6 million in the U.S. in 2018 and is expected to rise to 8 million by 2030 . The samCurrently, the indication for mechanical circulatory support (MCS) treatment for RHF is for patients who are refractory to medical or surgical therapy , howeverThe pathogenesis of RHF can be divided into three major categories: isolated RV injury, pulmonary etiology, and the one secondary to LV failure . Addition = 69) documented the long-term mortality among patients with RV MI after the first year was at an additional 2/year to 3%/year through 10th year  are representative of isolated RV injury. Acute inferior MI patients with high-grade proximal occlusion of the right coronary artery tend to show severe RV ischemic dysfunction, which may result in higher in-hospital mortality . However0th year .Pulmonary pathogenesis, which caused by increased RV afterload inducing RV pressure overload and hypoxia, is a broad category. The representatives of this pathogenesis are pulmonary hypertension (PH) and acute pulmonary embolism (PE). Regarding PH, the world health organization (WHO) classification for PH and the European Society of Cardiology and European Respiratory Society guidelines for PH may help organize the topic , 13. In Group 1: pulmonary arterial hypertension (PAH) ;Group 2: left heart disease ;Group 3: lung disease ;Group 4: chronic thromboembolic disease ;Group 5: miscellaneous .n = 2,635) showed a survival rate among PAH patients, which was 85 ± 1%, 68 ± 1%, 57 ± 1%, and 49 ± 1% at 1, 3, 5, and 7 years from diagnosis, respectively (n = 679) described that estimated survival at 1, 2, and 3 years was 93% , 91% , and 89%  in operated patients (n = 404), and only 88% , 79% , and 70%  in not-operated patients (n = 275).It should be noted here that the most prevalent group is group 2 (68%), which is the group of PH due to left heart disease, such as systolic and diastolic dysfunction of LV . Therefoectively . The morAs noted earlier, the RV function has a close interactive relationship with the LV function. As a result, the cause of the RHF in this pathogenesis could be decreased RV contractility and/or RV pressure overload. Cases are equally distributed in a wide variety of causes, such as myocarditis, LVAD support, ischemic disease, and mitral/aortic valvular heart disease; however, as long as this pathogenesis is secondary, the MCS for RHF is considered after or while receiving the LV treatment. Also noted earlier, this pathogenesis will include the patients with group 2 PH. Particular attention should be paid to the HF with preserved ejection fraction (HFpEF). The initial step should be made to treat RHF due to HFpEF after or while receiving the LV treatment; however, the treatment for HFpEF is still limited. Several efforts are undergoing in both medical and device-based treatment –18. Regaet al., the treatment mechanism of MCS devices for acute RHF can be divided into two categories; direct RV bypass and indirect RV bypass  is a U.S. FDA-approved, 22 Fr micro axial pump mounted on an 11 Fr catheter  and post-cardiotomy or post-MI patients with RHF (n = 29). The primary endpoint was survival at 30 days, hospital discharge post-device explant, or transition to the subsequent therapy, and was achieved in 73.3% of the study population. The total duration of device support in this study was ~ 3 days. The major adverse events at 30 days were major bleeding (60%) and hemolysis (13%). PA perforation occurred in one patient, which led to hemothorax, and was likely caused by the guidewire used during the device positioning. No PE was reported.The efficacy of the Impella RP was investigated in a prospective study, the RECOVER RIGHT study, in 2015 –25. The ® systems  and Impella RP (n = 20) reported that in-hospital mortality was 50% , formerly called TandemHeart, is an extracorporeal continuous-flow (CF) centrifugal flow pump with a magnetic pivot bearing , the LifeSPARC Pump is often used with the ProtekDuo cannula percutaneously via the right internal jugular vein  who went through the implantation with this system, during the mean length of support of 10.5 ± 6.5 days, 23% of patients were successfully weaned, 35% required conversion to either a surgical temporary extracorporeal RVAD (sRVAD) or durable implantable RVAD, and 41% did not survive . Another® system  is developed to permit extracorporeal life support circuit to be wearable, and the system consists of LifeSPARC pump, ProtekDuo® cannula, VoyagerVest®, and TandemLung® , Rotaflow II® , CAPIOX® , and MERA® Centrifugal Blood Pump   . Due to , Japan) , 38. Ant, Japan) . The adv, Japan) . The sysThe clinical outcome data of using VA-ECMO to isolate RV failure pathogenesis is limited to small cases studies –41; howe® (HVAD) from the global market in 2021; therefore, HeartMate 3® (HM3)  is the only U.S. Food and Drug Administration-(FDA) approved LVAD in 2022. HM3 is a CF centrifugal pump with full maglev bearing, displacing volume of 80 ml. For the anatomical limitation, the placement of the right pump may be a concern  announced that it was withdrawing the HeartWare Ventricular Assist Device concern . In one  concern . The pum concern . As a re concern , 45, 46. concern .In the same study of 14 patients who received dual HM3 implantation , five pa®  Soft Tissue Patch and placed in the right pleural space. Graft downsizing was done in three cases, and pump thrombosis was observed in three patients . The RVAD was implanted to the RA using the spacer and was wrapped with a Gore-Texpatients . The relThe authors also suggested that the extremely low thrombosis risk of the HM3 as an LVAD may explain this phenomenon . The maj®  is a paracorporeal pneumatic-drive pulsatile device with a lineup of different pump sizes that cover pediatric to adult  with different valves . For the variety of the pump sizes, dual Excor has been used as a BVAD, especially in the pediatric population  is a pneumatically driven pulsatile TAH with independent ventricles that are capable of providing a flow of more than 9 L/min  . Additio® TAH  is a pulsatile TAH that is electro-hydraulically driven  study showed that three out of four PAH patients who underwent bridge to recovery therapy successfully survived to VA-ECMO decannulation   . In addi 7 days) –69. Besi 7 days) ; howeverAcute PE and some of PH may need to be treated as acute RVF. For example, a post-operative period in CTEPH (group 4), and acute respiratory distress syndrome (ARDS) (group 3). The most suitable treatment option is indirect RV bypass with VA-ECMO. The 2019 European Society of Cardiology guidelines for the management of acute PE defined high-risk PE patients as having hemodynamic instability, PE severity index class III-V or simplified PE severity index ≥ 1, RV dysfunction on transthoracic echocardiogram or computed tomography pulmonary angiography, and elevated cardiac troponin levels. Furthermore, the guidelines suggest VA-ECMO therapy as class IIb, evidence level of C, in combination with surgical embolectomy or catheter-directed treatment and use of rapid short-term support , 72. OneConversely, a group from China reported in its subgroup analysis that the earlier ECMO treatment was associated with lower in-hospital mortality and significant overall survival . In casen = 39) reported that patients who received percutaneous RVAD with ECMO therapy had significantly lower in-hospital and 30-day mortality than patients treated with invasive mechanical ventilation only  were all reported as predictors for the RHF requiring RVAD , destination therapy (OR: 1.69), INTERMACS profiles 1–2 (OR: 1.60), and estimated glomerular filtration rate > 10 mL/min/1.73 ming RVAD .The RV MCS device selection during long-term LV support may largely depend on the duration of the RV support. Unplanned temporary RVAD use was reported with successful RVAD weaning rates of over 60% with a median support duration of 13–17 days , 94–96. As for long-term biventricular support, as discussed, the situation is rare, but it does exist. The options are limited due to the lack of durable MCS devices designed explicitly for RVAD. Currently, these options are: the off-label implantation of CF LVAD as an RVAD ; a paracorporeal pulsatile ventricular assist device as a biventricular support configuration ; and TAH (SynCardia TAH or Aeson TAH). For the timing of RVAD intervention, severe late RHF, which is defined by the requirement for an RVAD at months 3–12, is very rare . HoweverAs for the predictors for RHF, several research efforts are ongoing. The PA pulsatility index predicted the early RHF with a cutoff value of 2.0  . The RV There seems to be major three work fields that should have explored. First, the development of specifically designed, durable RVAD may be required. The specifically designed ventricular assist device that is able to operate on both sides of the heart, such as the Cleveland Clinic Universal Ventricular Assist Device UVAD, , is seenSecond, mobility of percutaneous RVAD must be improved. Currently, Impella RP is inserted from femoral vein because of the inlet of the cannula is designed to place in IVC and 11 Fr sheath (15 Fr outer diameter) stays at cannulation site, therefore, not suitable for rehabilitation. As for ProtekDuo cannula, 29 Fr cannula is inserted from right jugular vein; however, the large-bore cannula may still limit patients' outcome.® system is applicable for this category.Third, the oxygenation support with RVAD may be interesting field to explore. RVAD circuit connecting to membrane oxygenator, known as Oxy-RVAD configuration, has been reported for use in the patient waiting for lung transplant . TandemLWith an increasing incidence of RHF in the last decade, the therapeutic and device options for this pathology remain unmet. While previously underestimated, the RV has triggered interest with the scope of better understanding of the underlying disease pathogenesis in order to provide potential therapeutic options and device solutions. With ongoing effort amongst multiple engineering and clinical groups, there has been a substantial spike in research interest and development of unique device-based target therapies.The device selection for the shorter support duration seemed to have progressed to less invasive. To provide less invasive MCS therapy for RHF, the prediction for the support duration increases its importance. In the LV failure pathogenesis, more than 98% of patients received their LVAD therapy with centrifugal pumps in 2020, and more than 83% of patients were implanted HM3 . This trp = 0.01)  , howeverp = 0.93)  . AdditioFor long-term RVAD support, the currently available option is mainly limited to HM3 off-label use. The most concerning issue with this treatment is RVAD pump thrombosis. Regarding the necessity of outflow graft downsizing, one study operated the HM3 RVAD with a mean RVAD speed of 4,991 rpm and mean RVAD flow of 4.3 L/min . It was Moreover, in this review, we discussed about one-to-one correspondence treatment strategy for each pathogenesis; however, in the real clinical world, the most of the patients are expected to have multiple pathogenesis. For example, the patient in acute exacerbation of American College of Cardiology/American Heart Association stage C heart failure with comorbidity of severe chronic obstructive pulmonary disease, may not be a rare case. Therefore, there may be a situation that LV is not bad as receiving LVAD therapy but RV requires MCS device, to overcome the acute decompensation. For these patients, applying the algorithm for RV MCS device us may be helpful .Lastly, we did not include the RHF after HT because of the complexity of the mechanism and pathogenesis; however, the importance of MCS therapy for RHF is increasing. Moreover, since the first successful human HT was reported in 1967 in South Africa, more than 120,000 patients have received HT therapy , and theTK: manuscript preparation. CM: critical manuscript review. KF: critical revision of article. JK: critical revision of article, approval of article. All authors contributed to the article and approved the submitted version.The Universal Ventricular Assist Device Program is supported by federal funding from the National Heart, Lung, and Blood Institute under grant 5R21HL133871 (to KF).Author KF is a co-inventor of Universal Assist Device. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MS declared a past co-authorship with one of the authors CM, KF, and JK to the handling Editor.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background and Objectives: The development and standardization of genome-wide technologies able to carry out high-resolution, genomic analyses in a cost- and time-affordable way is increasing our knowledge regarding the molecular bases of complex diseases like autism spectrum disorder (ASD). ASD is a group of heterogeneous diseases with multifactorial origins. Genetic factors seem to be involved, albeit they remain still largely unknown. Here, we report the case of a child with a clinical suspicion of ASD investigated by using such a genomic high-resolution approach. Materials and Methods: Both array comparative genomic hybridization (aCGH) and exome sequencing were carried out on the family trio. aCGH was performed using the 4 × 180 K SurePrint G3 Human CGH Microarray, while the Human All Exon V7 targeted SureSelect XT HS panel was used for exome sequencing. Results: aCGH identified a paternally inherited duplication of chromosome 7 involving the CNTNAP2 gene, while 5 potentially clinically-relevant variants were identified by exome sequencing. Conclusions: Within the identified genomic alterations, the CNTNAP2 gene duplication may be related to the patient’s phenotype. Indeed, this gene has already been associated with brain development and cognitive functions, including language. The paternal origin of the alteration cannot exclude an incomplete penetrance. Moreover, other genomic factors may act as phenotype modifiers combined with CNTNAP2 gene duplication. Thus, the case reported herein strongly reinforces the need to use extensive genomic analyses to shed light on the bases of complex diseases. Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by impaired social interaction and communication as well as repetitive and stereotyped behaviors, interests, and activities, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) ,2. The wThe causes of ASD remain largely unknown; however, several studies have shown that genetic and environmental factors play an important role in the etiology of these disorders. Currently, ASD is considered a complex disorder with multifactorial etiology . ApproxiFamily and twin studies indicate a strong involvement of genetic factors in the etiology of autism. Indeed, the concordance in monozygotic twins is 70–90%, while in dizygotic twins, it reaches 30%, and in siblings 3–19%. Furthermore, several studies show a recurrence rate of the disease in relatives of an affected person of about 5–8%, with a 25–40 times increase in risk compared to the general population. Although ASDs have a hereditary component in approximately 90% of cases, the genetic factors involved in the pathogenesis are still largely unknown ,11,12. AWe report the case of a male child of 3 years and 7 months, the second child of healthy unrelated parents A, born ahttp://www.ensembl.org/, accessed on 18 March 2022). The CNVs contained in the interval-based report generated by Agilent’s Cytogenomics software were analyzed using Alissa bioinformatic software (Agilent) consulting Clinvar , Decipher , Database of Genomic Variants , GeneCards , and OMIM . This aCGH analysis, carried out on the trio, highlighted the presence of a heterozygous duplication of paternal origin on chromosome 7, in the q35 region, ranging from position 146,754,255 to 147,587,796 (human assembly GRCh38), with an extension of 883.54 kb, involving Contactin Associated Protein 2 , LOC101928700, and MIR548F4 genes . The trio was analyzed using the 4 × 180 K SurePrint G3 Human CGH Microarray , with an average spacing of 13 kb, allowing an average resolution of 25 kb. The microarray was scanned on an Agilent G2600D scanner. Image files were quantified, and data were visualized using Agilent’s Cytogenomics software (V.4.0.3.12), and the human assembly utilized was GRCh38, hg38  and ClinVar  databases. Their pathogenicity was further assessed using the Varsome tool . Through WES analysis, we obtained an average of 1.9 Gb/sample, being equivalent to about 34 million sequences/sample. After reads alignment and variants calling, about 50 k variants/sample were identified. The obtained sequencing specifications are summarized in Moreover, WES was carried out on this family trio. A DNA library was prepared for each DNA sample using the Human All Exon V7 targeted SureSelect XT HS enrichment system , according to the manufacturer’s instructions and as previously reported ,9. Next-Many genes involved in brain development are related to autism spectrum disorder. The emerging synergism between a-CGH and WES is improving the identification of new variants potentially related to this disorder ,20,21,22CNTNAP2 gene, located on chromosome 7, cytoband q35 , also called NRXN4, is characterized by 24 exons, for a total length of about 2,304,636 Mb, with 24 transcripts and 286 orthologues. This gene encodes a member of the neurexin family, which functions in the vertebrate nervous system as cell adhesion molecules and receptors. In particular, CNTNAP2 is highly expressed throughout the brain and spinal cord. During human brain development, its expression is highest in the frontal and anterior lobes, striatum, and dorsal thalamus. This expression pattern recapitulates the cortico-striato-thalamic circuitry known to modulate higher-order cognitive functions, including speech and language, reward, and frontal executive functions. In the human cortex, CNTNAP2 is expressed in layers II–V with enrichment in Broca’s area and other perisylvian brain regions. The enriched expression of CNTNAP2 in these brain regions, known to be important for speech and language, is consistent with the emerging role of CNTNAP2 in normal language development in humans [In this case, the n humans .CNTNAP2 has been implicated in multiple neurodevelopmental disorders, including Gilles de la Tourette syndrome [CNTNAP2 gene with the autism spectrum disorder [https://gene.sfari.org, accessed on 18 March 2022), which includes all the risk genes for autism, reports it as a strong syndromic candidate. This category includes genes whose variants show a functional effect in genome-wide association studies and whose mutations are related to an increased risk of developing autism. In particular, the CNTNAP2 gene has a score of 2, which underlines that variants present in this gene could have a functional effect. Studies on mouse models have shown that alterations in candidate genes for ASD (including CNTNAP2) induce an altered density of dendritic spines that depends on the specific genetic modification, age, and brain region [CNTNAP2 in a child with ID, ADHD, ASD, and speech impairment. These phenotypic traits correlate with CNTNAP2 deficiency disorder. The CNV of maternal origin involved a complete duplication of exon 2, which may negatively impact protein folding and/or protein-protein interactions. In particular, exon 2 encodes part of the discoidin homology domain, which is found in the extracellular portion of CNTNAP2 and mediates protein-protein interactions [CNTNAP2, could significantly increase the risk of comorbid epilepsy/tics in patients with non-syndromic ASD [https://decipher.sanger.ac.uk/, accessed on 18 March 2022) reports a 746.21 kb duplication in heterozygosity of likely pathogenic significance  ranging from position 146,754,255 to 147,500,463 with unknown parental origin. Moreover, a second patient  with intellectual disability showed a smaller duplication of 289.15 kb  of maternal origin and uncertain clinical significance, and 3 patients affected by intellectual disability and speech impairment, showed smaller duplications that include the CNTNAP2 gene . Only in patient 385,944 was the alteration of paternal origin; the others are of unknown origin. Although the number of CNTNAP2 gene deletions with clinically relevant significance is higher than duplications, as observed in the literature and by databases such as DECIPHER, the crucial role that duplications may play in the clinical manifestation of neurodevelopmental disorders cannot be excluded. It would be useful to understand if the variants identified in the patient have functional consequences on protein folding or protein/protein interactions. Furthermore, changes in the CNTNAP2 gene dosage have been shown to be associated with neurodevelopmental disorder-related phenotypes [syndrome , schizopsyndrome . In partdisorder ,27,28; in region . A studyractions . In the omic ASD . FinallyACTN3 gene. This variant is a nonsense substitution able to cause a premature stop codon. It is currently reported as a variant of uncertain significance (VUS) both in ClinVar and according to ACMG/AMP  classification. ACTN3 encodes for alpha-actinin-3, a protein expressed in type-II muscle fibers, and that has been associated with performance phenotype, including speed, exercise adaptation, exercise recovery, and sporting injury risk [Within the variants identified by WES, only one was in homozygous status, the two parents being both carriers: the c.1729C>T p.(Arg577Ter) (aka R577X) in the exon 15 of the ury risk . In partury risk . It has ury risk . Indeed,ury risk . The XX ury risk . Thus, bMTHFR) polymorphism associated with an increased risk of hyperhomocysteinemia that is, in turn, a risk factor for different cardiovascular diseases [MTHFR variant c.788C>T p. has been reported as a risk factor for schizophrenia development (Within the remaining 4 variants, one is a common functional Methylenetetrahydrofolate reductase (diseases . This vadiseases ,38,39,40elopment , and it HBG1, PAH, and MPO genes. All of them are related to recessive diseases, thus suggesting a carrier status for these diseases.The last 3 variants are heterozygous variants classified as pathogenic and found in the CNTNAP2 gene, we more thoroughly analyzed this gene to detect the presence of additional variants of maternal inheritance that may contribute to diseases development in the proband. As shown in CNTNAP2 variants also present in the mother are common polymorphisms currently associated with a benign clinical significance.Finally, since a-CGH analysis has highlighted a duplication in a region of chromosome 7 in the proband that has been inherited from the father and involves the CNTNAP2 duplication by aCGH that may be related to the patient’s phenotype. Since it is paternally inherited, even though we cannot exclude the incomplete penetrance of this variant, we hypothesized the presence of additional genetic variants able to impact clinical phenotype. Thus, we carried out WES and identified some potentially interesting variants. Even if WES analysis did not highlight a pathogenic variant that may explain the clinical phenotype of the patient described herein, we underline again the need to integrate diagnostics to improve the comprehension of the molecular bases of complex diseases. First, the absence of pathogenic variants identified by WES analysis may reinforce the role of the CNV alteration. Moreover, risk variants able to act as phenotype modifiers may also be highlighted as contributing to the final clinical phenotype observed in the patients. Finally, it has to be noticed that variants classification varies over time and may change due to knowledge increase. Thus, a re-evaluation of the genomic data may clarify the molecular bases of the observed disease in the future.In recent years, great progress has been made in the attempt to clarify the etiology of ASD. The significant percentage of familial cases associated with a high concordance rate in monozygotic twins supports a genetic basis for neurodevelopmental disorders and ASD in particular. On the other hand, the functional significance of CNVs affecting single genes and/or genomic regions is still remarkably incomplete, making diagnostic processes and genetic counseling difficult. Consequently, the discovery of significant genes, which can be considered causal or associated with ASD, represents a necessary step in the diagnostic procedure for a better understanding of their pathophysiology. In fact, a deeper knowledge will help to better classify the clinical characteristics of patients and the mechanisms underlying their clinical manifestations. In particular, a-CGH and WES represent important tools for identifying new disease genes and new alterations in causative or disease-associated genes. This, in turn, will improve the correlations between alterations affecting certain genes and specific phenotypic characteristics, expanding knowledge of the molecular basis of these complex disorders. The interaction between a-CGH and NGS panels or WES in individuals with ASD may be considered an added value to the diagnostic process, although not yet available in routine clinical diagnostic testing. In the case described herein, we detected a Considering the wide heterogeneity of these disorders, both in terms of behavioral and genetic characteristics, further efforts are needed to explore the possible role of environmental and epigenetic elements. Future studies in close collaboration between divisions of neuropsychiatry and genetics laboratories should be necessarily conducted to shed light on these aspects and their complex connections, thus supporting a better ASD patient diagnosis and management.


Solitary plasmacytoma of bone (SPB) is an isolated plasmacytoma of bone origin, most commonly seen in the elderly, with a poor prognosis. So far, there is no precise nomogram to predict the overall survival (OS) of elderly patients with SPB. Our goal is to construct and validate a nomogram for elderly patients with SPB.  This study collected all elderly patients with SPB in the Surveillance, Epidemiology and End Results (SEER) database from 2000 to 2018, and the variables included were age, sex, race, marital status, primary site, grade, stage, surgery, chemotherapy, and radiotherapy. Independent prognostic factors were identified using univariate and multivariate Cox analysis. The nomogram was constructed to predict 1-, 2-, and 3-year OS of elderly patients with SPB. The receiver-operating characteristic (ROC) and the calibration curves were used to differentiate and calibrate the nomogram. The clinical validity of the nomogram was evaluated by decision curve analysis (DCA). The total OS scores of all elderly SPB patients were calculated and divided into two risk subgroups for comparison.  A total of 1837 patients diagnosed with SPB were screened from the SEER database, with a final inclusion of 1180 patients (age ≥ 60 years). Age, radiotherapy, and marital status were significantly correlated with OS. These characteristics were further incorporated into the creation of the nomogram for predicting 1-, 2-, and 3-year OS of elderly patients with SPB. For this predictive model, the area under the ROC curves, calibration curves, and DCA have good performance in terms of differentiation, consistency, and validity, respectively. In addition, patients in the high-risk group (≥96) had a worse prognosis than those in the low-risk group (<96).  We constructed a nomogram and a risk classification system that could provide an intuitive and effective tool for clinicians to better predict the OS of elderly SPB patients. Plasmacytoma is a primary and systemic malignancy originating from the bone marrow and characterized by clonal proliferation of plasma cells. Plasmacytomas include extramedullary plasmacytoma (EMP), solitary plasmacytoma of bone (SBP), and multiple myeloma (MM) . SBP is Several studies , 9 have We screened all cases of SPB from the SEER database using the International Classification of Diseases for Oncology (ICD-O-3) code 9731/3. Cases with peripheral blood, bone marrow, or other extramedullary organ involvement and those with incomplete information were excluded from this study. The flow chart for data selection is detailed in p values < 0.05 were considered to be statistically significant.We collected 1180 cases and randomly divided them into training cohorts (70%) and validation cohorts (30%). The patient's optimal cut-off value was obtained by X-tile software . Independent prognostic factors were identified using univariate and multivariate Cox analysis. The nomogram was constructed to predict 1-, 2-, and 3-year OS of elderly patients with SPB. We constructed receiver-operating characteristic (ROC) curves and calibration curves to verify the differentiation and calibration of the nomogram and evaluated the validity of the model using decision curve analysis (DCA) , 13. In Based on the inclusion and exclusion criteria, we ultimately included 1837 patients with SPB from the 2000-2018 SEER database, of which a total of 1180 were aged ≥60 years. The training cohort and the validation cohort consisted of 828 and 352 individuals, respectively, for the construction of the nomogram and validation. Patients were predominantly male  and white (79.2 and 85.5%), had a marital status of yes (67.3 and 63.1%), had undergone radiotherapy (77.4 and 75.3%), and localized (82.5 and 82.7%). Concerning the pathologic grades and primary site, pre-B cell (96.9 and 98.0%) and trunk (75.4 and 80.7%) were the most common. p ≤ 0.001), marital status (p ≤ 0.001), and radiotherapy (p ≤ 0.001) were significantly associated with OS, while patients sex, race, primary site, stage, grade, surgery, and chemotherapy were not significantly correlated with OS. Because the p values of surgery in the cox univariate and log-rank analyses were 0.083 and 0.026, respectively, and because of the importance of surgery in clinical care, we also included surgery in the Cox multivariate regression analysis to avoid missing variables. The Cox multifactor regression analysis further showed that age , marital status , and radiotherapy  were independent prognostic factors for OS in elderly patients with SPB. The Kaplan-Meier curves of all variable factors in OS were drawn  and low-risk (<96) by the X-tile software. Survival curves for both the training and validation groups showed good prognostic stratification, with the high-risk group having a worse prognosis than the low-risk group .Solitary plasmacytoma of bone is a type of malignant plasmacytoma disease with a rare nature and a relatively high recurrence rate , 15. MorIn this study, we found that age, marital status, and radiotherapy were independent prognostic factors for OS in elderly patients with SPB, and we further developed a nomogram to predict survival outcomes, which showed good predictive performance for both internal and external validation. As shown in the red line marked in p < 0.0001), with an increasingly worse prognosis with increasing age. Many studies [We found a significant difference in survival trends among patients aged 60-70, 71-82, and >82 years on the Kaplan-Meier curve ( studies –22 have  studies  and Jawa studies , age (>6 studies , which s studies , blacks Marital status, as a sociodemographic factor, has been well documented as an independent prognostic factor for multiple cancer types –28. MariSolitary plasmacytoma of bone is highly sensitive to radiation, and radiotherapy has become the first-line treatment for most patients at doses of up to 40-50 Gy , with exThere are several limitations to this study. First, as a retrospective study, it inevitably led to a degree of bias that needs to be further validated in subsequent prospective studies. Second, we used the same central database for both internal and external validation, and it would have been preferable to validate the nomogram using data from multiple centers to increase its reliability. Third, considering the lack of laboratory tests, gene expression items, radiotherapy doses, and surgical methods in the SEER database, future studies should attempt to include these factors to create a more effective nomogram of SPB in the elderly.Age, radiotherapy, and marital status were identified as independent prognostic factors for elderly SPB patients, and surgery was excluded. We developed a nomogram for estimating OS at 1, 2, and 3 years and established a corresponding risk classification system based on 1180 cases extracted from the SEER database. The nomogram is not only well discriminated and calibrated but also has strong clinical application.


The purpose of this systematic review was to understand Indian mothers’ milk composition and report changes in it over the past 100 years. A review was conducted in accordance with PRISMA and registered with PROSPERO (CRD42022299224). All records published between 1921 and 2021 were identified by searching databases Google Scholar, ResearchGate, PubMed, and the Cochrane Database of Systematic Reviews. All observational, interventional, or supplementation studies reporting macronutrients  in milk of Indian mothers, delivering term infants, were included. Publications on micronutrients, preterm, and methods were excluded. Milk was categorized into colostrum, transitional, and mature. In all, 111 records were identified, of which 34 were included in the final review. Fat ranged from 1.83 to 4.49 g/100 mL, 2.6 to 5.59 g/100 mL, and 2.77 to 4.78 g/100 mL in colostrum, transitional, and mature milk, respectively. The protein was higher in colostrum (1.54 to 8.36 g/100mL) as compared to transitional (1.08 to 2.38 g/100 mL) and mature milk (0.87 to 2.33 g/100 mL). Lactose was lower in colostrum (4.5–6.47 g/100 mL) as compared to transitional (4.8–7.37 g/100 mL) and mature milk ranges (6.78–7.7 g/100 mL). The older studies (1950–1980) reported higher fat and protein in colostrum as compared to subsequent time points. There were variations in maternal nutritional status, diet, socioeconomic status, and regions along with study design specific differences of time or methods of milk sampling and analysis. Additionally, advancements in methods over time make it challenging to interpret time trends. The need for conducting well-designed, multicentric studies on nutrient composition of Indian mother’s milk using standardized methods of sampling and estimation for understanding the role of various associated factors cannot be undermined. Rapid urbanization, increasing food availability, and a sedentary lifestyle are a part of a nutrition transition India is undergoing, along with facing a triple burden of malnutrition. Nearly 24% of women in the reproductive age-group are overweight, 18.7% are underweight, and 57% are anaemic in India , and IndEarly initiation and exclusive breastfeeding significantly reduce neonatal mortality ,8. HumanThe composition of human milk is variable and largely depends upon maternal, infant, and environmental factors ,33,34,35In India, maternal diets are generally plant-based and may have macro and micronutrient imbalances. This could affect the macronutrient composition of human milk. Studies have shown that with plant-based diets in populations with food insecurity, breast milk fat content may be suboptimal ,50,54. EIt becomes imperative to understand human milk composition and the various factors associated with its composition to formulate more comprehensive guidelines for the promotion of infant care practices during the first 1000 days. This is important for optimum growth and development of infants, irrespective of socio-economic status and regional variation. The work in the Indian subcontinent is limited on composition of human milk. To the best of our knowledge, to date, there has been no systematic review to assess the changes in breast milk composition of Indian mothers. An effort has been made to compile all the published studies on human milk composition of mothers of Indian origin in the last century. In addition, this review intends to critique the evidence of associated data on maternal nutritional status, their diet, the SES, and gestational age. A systematic review with an assessment of heterogenous trials in accordance with protocols of Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines was conducted . This reAll observational, interventional or supplementation studies involving any nutrient in human milk of Indian mothers/in mothers of Indian origin published or accepted in peer reviewed journals were included during initial screening and assessed in detail for eligibility;Only studies which reported any macronutrient  were included for detailed assessment;Studies conducted on human milk in Indian mothers of term infants were included. Those records which reported both term and preterm mothers were also included but only term data was included in this review;Studies reporting any type of milk  from Indian mothers were included;Studies based on a milk macronutrients composition in maternal disease condition but had a control group as well were included. Data from control group from such publications was referred to for this review;Publications based on conferences, technical reports, Letters to the Editor with study findings, and data reported in Indian Medical Gazette on nutrient composition of Indian mother’s milk were also included.Inclusion Criteria:Animal and laboratory in vitro studies were excluded;Human milk nutrient composition of mothers of any other nationality other than Indian were excluded;All analytical/methodology papers, review articles, duplicate papers, or the records not reporting macronutrients were excluded;Publications where milk macronutrient composition was only from mothers with a disease condition were excluded.Exclusion Criteria:n = 14), methodological studies (n = 1), studies where human milk was not evaluated (n = 2), nutrient data not reported (n = 2), full text could not be retrieved (n = 3)). An eligibility assessment was conducted for remaining 89 publications. Further, based upon detailed reading, 55 records were excluded owing to either being on only preterm mothers (n = 3), reporting data on nutrients other than protein/fat/carbohydrates (n = 47) or based on analytical methods (n = 2), duplicate papers (n = 2), and data only from mothers with disease condition (1). All studies were revisited by SG for identifying any other relevant studies and validating search. Hence, a total of 34 records have been included in this systematic review. The units reported by all the above studies was either g/100 mL or g/100 g or% of nutrient in human milk. Since these units are comparable, all 34 records were included in the review (n = 6) and P2 (n = 40). Control group data (with no disease condition) was included from 4 studies which reported milk macronutrients from mothers with a disease condition  based on the title and/abstract . Followie review  [43,49,5eri-Beri , with cheri-Beri , pregnaneri-Beri , anaemiaeri-Beri ). Suppleeri-Beri . Studieseri-Beri ,87. During initial screening, the 34 records were examined by one reviewer (DK) to assess and extract data on first author, year of publication, sample size, geographical location, type of milk, macronutrients included in sample collection, method of nutrient estimation and key findings. All studies were further categorized on human milk data available for colostrum, transitional milk, and mature milk. SG and GV participated during detailed screening of all records and any differences between reviewers were discussed and consensus for eligibility and inclusion was made.https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools (last accessed on 1 February 2022) for systematic evidence of records [n = 29) was fair. Two studies were rated good [The quality of 34 included records were assessed using study quality assessment tools by National Heart, Lung, and Blood Institute  records reported macronutrients. For ease in reporting, the number of publications is presented decade wise  and Western regions of India (n = 10) followed by Northern (n = 9), Eastern region (n = 2), and Central India (n = 1). There was one record from Burma [The maximum number of records were reported from Southern , milk sampling was completed in the morning; only two studies collected samples (5.9%) in the afternoon. The remaining records (35.3%) did not mention the time of milk collection  and two were on high SES [n = 10) did not mention the SES. Only 13 records mentioned the nutritional status of mothers, of which six used Body Mass Index (BMI) for classification [In majority of records  have reported mature milk fat (n = 12) reported fat between 2.7 and 3.74 g/100 mL [n = 12) studies reporting similar ranges were mainly conducted on mothers belonging to poor SES. All 17 studies collected milk sample at different time points and used different methods of estimation  in early milk (3rd–10th day pp) collected from low SES South Indian mothers  Figure c. SimilaThe protein content in mature milk was reported highest in earliest studies in the 1930s  and 1940The major carbohydrate in human milk is lactose and it is also the most measured carbohydrate in the studies published on Indian mothers in the last century. We included 19 records reporting lactose content . A totalHuman milk typically constitutes 7% carbohydrates (mostly lactose), up to 5% fat, 0.9% proteins, and lesser quantities of vitamins and minerals . It is rThe primary objective of this review was to understand the Indian mothers milk composition and report any changes over time. It was noted that older studies from the 1950s–1980s reported higher fat and protein in colostrum as compared to later time points. However, milk is well known to be an extremely variable biological fluid which varies between and within populations, across lactation, within mother during a single nursing and throughout the day ,93,94,95Apart from methodological factors, human milk is known to be influenced by maternal nutritional status, dietary intake, socioeconomic status, and regional variations ,41,50,96Regarding fat, none of the records compared milk fat from mothers in different BMI categories. Based upon individual records, two studies on undernourished mothers reported lower fat in mature milk ,74 as coFrom this review, only three studies assessed the association between maternal haemoglobin and milk macronutrient composition ,83,90. TA majority of the studies in the 1950s ,67,68,69Two studies reporting type of diet  had no significant difference in protein content of breast milk ,81. Howe(n = 14) were conducted on women belonging to lower income group with eight studies compared data from different income groups. Studies conducted in late 1950s [In this review, most of the studies te 1950s ,69,70 dete 1950s ,82. Howete 1950s ,75. It iIt becomes important to understand the entire human milk biological system for better implication of this for vulnerable segment of the population and to cover women belonging to very poor socio-economic status, different nutritional status, residing in different geographical locations with regional and ethnic differences ,97. The India is historically a natural promoter of breastfeeding. This is the first ever century based systematic review published on Indian mothers’ milk macronutrients composition. With high rates of infant and neonatal mortality, along with a triple burden of malnutrition, this review is a timely compilation of milk macronutrient composition across time, from different regions and states of India, across stages of lactation, SES, maternal nutritional status, and diets. The limitation of this review was the large heterogeneity in sampling and estimation along with limited records focussing on the impact of maternal diets, nutritional status, or regional differences on the macronutrient composition on milk. This impeded our ability to not only conduct a meta-analysis but also draw time trends. This limitation surely highlights the future need for conducting well designed, multicentric studies using standardized methods on Indian mothers’ milk composition.This is the first systematic review studying changes in macronutrient composition of Indian mothers’ milk over the past century and reporting the role of multiple factors impacting it over time. There are individual records with data from mothers belonging to different regions, socio-economic strata along with variations in gestational age, lactational stage, maternal dietary intake, and nutritional status. The studies prior to the 1980s reported the highest fat in the colostrum (vs. other stages of lactation) than that reported by recent studies. Protein was the highest in colostrum as compared to other postnatal stages of lactation in all the studies. Along with other methodological differences, the phase of milk collection within the same lactational stage may be an important factor. With India undergoing a socio-economic, demographic, and nutritional transition, along with recent advancements in methodological techniques , more standardized research in this area is necessary. A similar understanding for micronutrient composition of human milk is desirable considering the micronutrient deficiency prevalence.