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Treatment options have expanded rapidly and widely in the past two decades for patients with multiple myeloma. Triplet novel agent-based induction regimens have been accepted as the standard practice wordwide over the last decade both for transplant-eligible and non-eligible patients. The addition of anti-CD38 monoclonal antibodies as part of quadruplet regimens has led to even deeper and longer-lasting responses. The impressive results shown by the quadruplets havebeen practice-changing where accessible in recent years. Chimeric antigen receptor T cell therapy and bispecific antibodies are being tested in the upfront setting and have the potential to once again shift the paradigm of treatment of newly diagnosed MM.

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The standards of care for the initial treatment of patients with newly diagnosed multiple myeloma (NDMM) who are eligible for high-dose melphalan and autologous stem cell transplantation (HDM-ASCT) include highly active triplet and quadruplet regimens based on proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. These regimens are resulting in improved outcomes and increasingly high rates of minimal residual disease (MRD)-negative responses without HDM-ASCT as part of the upfront therapy. Furthermore, recent randomized studies have shown that, while transplant-based approaches as a frontline therapy result in significantly longer progression-free survival compared to non-transplant approaches, this has not translated into an overall survival benefit. Given these developments, and in the context of the treatment burden of undergoing HDM-ASCT, in addition to the acute toxicities and long-term sequelae of HDM, which are associated with the genotoxicity of melphalan, there is an increasing rationale for considering deferring upfront HDM-ASCT in select transplant-eligible patients and saving it as a treatment option for later salvage therapy. Here, we review the latest clinical trial data on upfront or deferred HDM-ASCT and on the activity of quadruplet induction regimens, including rates of MRD-negative responses, and summarize emerging treatment approaches in the upfront setting such as the use of MRD-directed therapy and alternatives to HDM-ASCT.

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Heterotopic pregnancy (HP) is a rare occurrence in natural pregnancies. However, it can be a life-threatening condition and should be taken into account in all assisted reproductive treatments. Diagnosis and treatment of ectopic pregnancy are challenging issues in patients with HP. Here, we report a rare case of quadruplet HP following an in vitro fertilization-embryo transfer with a viable twin intrauterine pregnancy and ruptured live twin left tubal ectopic pregnancy. A 35-year-old woman (gravida 5, para 1, ectopic pregnancies 2, and abortion 1) was presented to the Emergency Department of Arash Women's Hospital (Tehran, Iran) in March 2021 with abdominal pain. The patient was at six weeks and five days of pregnancy following in vitro fertilization-embryo transfer. Transvaginal sonography (TVS) revealed a live twin intrauterine pregnancy with a ruptured live twin left tubal ectopic pregnancy. The latter was removed via laparotomy to preserve the intrauterine pregnancy. The patient subsequently delivered a female infant at 38 weeks of pregnancy.

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In August 1950, Mrs Betty Sara, aged 29 years, was confined of quadruplets in the town of Bellingen, New South Wales, which is 500 km north of Sydney. All four babies were delivered vaginally, after a confinement lasting over two and a half days.

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In this article, we show that mono/oligonucleotide quadruplets, as basic structures of DNA, along with our classification of trinucleotides, disclose an organization of genomes based on purine-pyrimidine symmetry. Moreover, the structure and stability of DNA are influenced by the Watson-Crick pairing and the natural law of DNA creation and conservation, according to which the same mono- or oligonucleotide insertion must be inserted simultaneously into both strands of DNA. Taken together, they lead to quadruplets with central mirror symmetry and bidirectional DNA strand orientation and are incorporated into Chargaff's second parity rule (CSPR). Performing our quadruplet frequency analysis of all human chromosomes and of Neuroblastoma BreakPoint Family (NBPF) genes, which code Olduvai protein domains in the human genome, we show that the coding part of DNA violates CSPR. This may shed new light and give rise to a novel hypothesis on DNA creation and its evolution. In this framework, the logarithmic relationship between oligonucleotide order and minimal DNA sequence length, to establish the validity of CSPR, automatically follows from the quadruplet structure of the genomic sequence. The problem of the violation of CSPR in rare symbionts is discussed.

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BACKGROUND: We discuss the challenges of multiple pregnancy at very advanced reproductive age. CASE PRESENTATION: We present the case of a quadruplet pregnancy at the maternal age of 65 following in-vitro fertilization (IVF) with donor eggs and sperm, involving cross-border reproductive care. All children born were at 25 weeks' gestation and survived; however, poor neurodevelopmental outcome remains a major concern in one child. CONCLUSIONS: The use of reproductive technology to achieve a multiple pregnancy at such an advanced post-menopausal age generated a debate on ethical, psychosocial and medical questions. We share this debate and highlight the need to reconsider international guidelines for women of advanced reproductive age.

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INTRODUCTION: As we have just stepped into a new decade of hopes, the mountain of knowledge learned from multiple myeloma (MM) remains unmatched among cancers. In the last decade alone, this rapid-sequence learning curve has led to regulatory approvals of eight drugs with mechanisms of actions representing five different areas of cell biology some of which made to the frontline setting, sparking debates about how to best sequence them in the treatment continuum of induction, consolidation, and maintenance and gained momentum with the realization of the implications of an effective upfront therapeutic approach with potential impact on survival. AREAS COVERED: This review was written with an intent to introduce the reader to the current treatment approach of a newly diagnosed myeloma patient and acquaint with promising targets and mechanistic strategies. Medline and clinicaltrials.gov databases (2000-2020) and relevant meetings (ASH, ASCO, EHA, ESMO, IMW) reports were queried and guidelines (IMWG) were reviewed to distill to expert opinion in an inundating field. EXPERT OPINION: Future holds promise with new targets on the horizon. It is likely that the new age of myeloma will belong to quadruplets with the addition of acellular or cellular biologics to first-generation novel agents, leading to new paradigms.

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I provide plausibly causal estimates of the effect of birth weight using data from the universe of twins, triplets, and quadruplets born between 1995 and 2000 in the United States. Infants from higher-order multiple births have lower birth weights, but experience smaller reductions in infant health when they are low birth weight. OLS estimates using a rich set of controls show that this result holds when comparing singletons to multiples and when analyzing historical data from before the widespread use of in vitro fertilization. These results suggest that the paradox of low birth weight remains even after controlling for unobserved maternal heterogeneity.

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Exclusive breastfeeding is currently recommended until at least 6 months of postnatal age, due to maternal breast milk (BM) unique composition and beneficial properties. In fact, BM modifies itself according to gestational age (GA) at birth, adapting its composition to neonatal requests during lactation. Multiple births represent about 3% of the whole pregnancies; such neonates result more vulnerable than full-term newborns, due to lower GA and birth weight (BW) and the higher incidence of perinatal complications. Although an adequate nutrition is fundamental for twins and other multiples, studies on this topic are lacking. We collected and analyzed BM from mothers of 19 twins and 5 triplets showing GA < 33 weeks and BW < 1500 g, comparing it to a control group of 28 preterm singletons. As a result, at GA ≤ 28 weeks, we observed that protein content is higher in BM for multiples (1.53 vs. 1.29 g per 100 ml), lactose concentration is greater in BM for singletons (6.72 vs. 6.34 g per 100 ml) and GA results the most relevant factor influencing BM protein composition. BM for multiples results higher in proteins and lower in lactose, if compared with singleton's samples; this could promote and sustain growth and organ development in this vulnerable category. BM from multiples shows a trophic and immunologic role, since these neonates often show lower GA and BW instead of singletons. These findings could help in optimizing nutritional strategies and improving BM individualized fortification.

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OBJECTIVE: To report a rare case of quintuplets with monochorionic male quadruplets and a single female after two-blastocyst transfer. DESIGN: Case report. SETTING: University teaching hospital. PATIENT(S): A 37-year-old gravida 1, para 1, presenting after two-embryo IVF with monochorionic male quadruplets and a single female. INTERVENTION(S): Ultrasound examinations and cesarean delivery. MAIN OUTCOME MEASURE(S): Successful delivery of five live-born infants at 28 weeks and 6 days of gestation for preterm labor. RESULT(S): The patient was diagnosed with quintuplets consisting of monochorionic male quadruplets and a single female after the placement of two embryos in blastocyst stage. She was followed closely with ultrasound examinations and hospitalized at 23 weeks' gestation. Cesarean delivery was performed at 28 weeks and 6 days of gestation, with eventual discharge of all infants in healthy condition. CONCLUSION(S): This case represents successful assisted reproductive technology quintuplets with monochorionic quadruplets and a co-sibling. Higher-order monozygotic pregnancies with monochorionic quadruplets are exceedingly rare and a potential complication of IVF.

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Objective: Triplet or higher-order multiple pregnancies are often caused due to ovulation induction. Spontaneous quadruplet pregnancy is a rare phenomenon which is associated with maternal and fetal complications. Here in, we report a spontaneous quadruplet pregnancy with no family history and as a result of an unwanted pregnancy. Case report: The patient was a 34-year-old, G4 L2 Ab1. She noticed being pregnant during breastfeeding, a spontaneous quadruplet pregnancy. There was no case of multiple pregnancies in her or her husband's family. In week 29 she was hospitalized due to the diagnosis of preterm labour. At 32 weeks and 4 days of gestation, because of the restart of labour contractions and dilatation development, she underwent a cesarean section. The outcome was the birth of 4 healthy neonates weighing between 1800 to 2100 gram and normal Apgar score. Conclusion: Quadruplet pregnancy can rarely occur spontaneously even unintentionally, and can reach the third trimester without prophylactic cerclage.

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RESUMEN Objetivo: Reportar un caso de embarazo cuádruple y revisar la literatura disponible con respecto a la edad gestacional en la que se identifica el tipo de placenta (mono o policoriónica) en la que finaliza el embarazo, el peso del recién nacido y la frecuencia del cuidado prenatal de este tipo de gestaciones. Materiales y métodos: Se presenta del caso de una mujer con embarazo cuádruple secundario a técnica de reproducción asistida, atendida en una institución de cuarto nivel de complejidad, ubicada en la ciudad de Bucaramanga, Colombia. Se realizó una revisión de la literatura publicada en las bases de datos Medline vía PubMed, Embase, SciELO y UptoDate® con los términos de búsqueda: "embarazo múltiple", "cuádruples", "atención prenatal" y "resultado perinatal". La búsqueda se limitó por idioma (artículos en inglés y español). Resultados: Se recuperaron 19 referencias que cumplían con los criterios de inclusión y de exclusión. No hay información sobre la frecuencia con la que se debe hacer el control prenatal. El tipo de placenta se pudo establecer entre las semanas 9 y 25; la edad gestacional varió entre 26 y 34 semanas. El peso varió entre 1.076 y 1.770 g. Los embarazos multigestación se acompañan frecuentemente de complicaciones maternas y perinatales. Conclusiones: El diagnóstico del embarazo cuádruple puede hacerse temprano en la gestación. Frecuentemente se acompaña de prematuridad y bajo peso al nacer. Se requieren estudios que evalúen el manejo más seguro y efectivo de esta condición.

ABSTRACT Objective: To report the case of a quadruplet pregnancy and conduct the review of the available literature regarding gestational age at which the type of placenta (monochorionic or polychorionic) is identified, the gestational age at which the pregnancy comes to an end, the weight of the neonate, and the frequency of prenatal care in this type of gestation. Materials and methods: Case report of a woman with a quadruplet pregnancy secondary to assisted reproduction technique, seen at a Level IV complexity centre in the city of Bucaramanga, Colombia. A review of the literature was conducted in Medline vía PubMed, Embase, SciELO and UptoDate® databases using the search terms "multiple pregnancy," "quadruplets," "prenatal care," and "perinatal outcome". The search was limited by language to articles in English and Spanish. Results: Overall, 19 references that met the inclusion and exclusion criteria were retrieved. There is no information on the required frequency of prenatal visits. It was possible to identify the type of placenta between 9 and 25 weeks; gestational age varied between 26 and 34 weeks. Weight varied between 1,076 and 1,770 g. Multigestation pregnancies are frequently associated with maternal and perinatal complications. Conclusions: Quadruplet pregnancies may be diagnosed early in the gestation. They are frequently associated with prematurity and low birth weight. Further studies are required in order to assess the safest and most effective way of managing this condition.

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For almost 50 years the conclusive explanation of Chargaff's second parity rule (CSPR), the equality of frequencies of nucleotides A=T and C=G or the equality of direct and reverse complement trinucleotides in the same DNA strand, has not been determined yet. Here, we relate CSPR to the interstrand mirror symmetry in 20 symbolic quadruplets of trinucleotides (direct, reverse complement, complement, and reverse) mapped to double-stranded genome. The symmetries of Q-box corresponding to quadruplets can be obtained as a consequence of Watson-Crick base pairing and CSPR together. Alternatively, assuming Natural symmetry law for DNA creation that each trinucleotide in one strand of DNA must simultaneously appear also in the opposite strand automatically leads to Q-box direct-reverse mirror symmetry which in conjunction with Watson-Crick base pairing generates CSPR. We demonstrate quadruplet's symmetries in chromosomes of wide range of organisms, from Escherichia coli to Neanderthal and human genomes, introducing novel quadruplet-frequency histograms and 3D-diagrams with combined interstrand frequencies. These "landscapes" are mutually similar in all mammals, including extinct Neanderthals, and somewhat different in most of older species. In human chromosomes 1-12, and X, Y the "landscapes" are almost identical and slightly different in the remaining smaller and telocentric chromosomes. Quadruplet frequencies could provide a new robust tool for characterization and classification of genomes and their evolutionary trajectories.

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INTRODUCTION: Hirschsprung's disease is a congenital colonic aganglionosis, usually presented as inability or difficulty in passing of meconium, chronic and persistent obstipation, maleficent feeding, vomiting, distension and lethargy. CASE PRESENTATION: We presented a case of an in-vitro conceived quadruplet premature neonate who presented with pneumoperitoneum caused by transverse colon spontaneous perforation and microcolon appearance of distal bowel, treated by resection and temporary colostomy turns to be a rare manifestation of Hirschsprung's disease. CONCLUSION: Assisted reproductive technologies increases chances for multiple pregnancies and may increase chance for major congenital anomalies. Rare manifestation of Hirschsprung's disease is spontaneous pneumoperitoneum which remains a surgical emergency. Delay in recognizing and treatment can significantly worsen prognosis. In neonate with intestinal perforation one should consider Hirschsprung's disease.

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O presente trabalho teve como objetivo descrever um caso de parto quadrigemelar em uma ovelha da raça Santa Inês. Em abril de 2013, foi atendida, em uma propriedade rural no município de Santa Cruz da Conceição, estado de São Paulo, uma ovelha da raça Sant Inês que havia parido quatro cordeiros. Nasceram três fêmeas, com pelagem marrom, branca e preta, e um macho, com pelagem preta. No período de uma hora após o parto, todos os cordeiros ficaram em pé e mamaram o colostro. A ovelha não rejeitou nenhum dos cordeiros...

The study aimed to describe a case of Santa Inês ewe having quadruplets. In April of 2013 on a farm in Santa Cruz da Conceição, São Paulo, a Santa Inês sheep that had calved 4 lambs was assisted. There were three females and one male, the females had brown coats, white and black, and the male had a black coat. Within 1 hour after birth all lambs were standing and suckled colostrum. The ewe did not reject any of the lambs...

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OBJECTIVE: To report a rare case of successful pregnancy and delivery of two pair of monozygotic twins (quadruplets). METHODS: We reported a Case Report of a 32-year-old nulligravida, who had had a previous twin pregnancy and was herself a twin assisted hatching. Prophylactic cervical cerclage sec. McDonald in the 23st week of pregnancy, hospitalization, and intensive care of pregnancy were performed. RESULTS: Successful pregnancy and delivery of two male and two female twins in the 34th week of pregnancy.

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BACKGROUND: To assess the risk of neonatal mortality and morbidity in twin, triplet and quadruplet pregnancies. METHODS: In a retrospective study, the neonatal outcome of all twin, triplet and quadruplet gestations delivered from October 2001 to September 2006 was reviewed. The neonatal outcome of triples and quadruplets was compared with a matched group of twins for gestational age. RESULTS: During a 5-year period, 511 sets of twin pregnancies, 42 sets of triplet and 5 sets of quadruplet pregnancies were studied. The mean of gestational age for twins, triplets and quadruplets were 33.92 ± 3.5 weeks, 30.92 ± 3.8 weeks and 31.60 ± 2.0 weeks, respectively, (P = 0.0001). Triplets and quadruplets weighed less than twins, (P = 0.0001). Neonatal mortality was 13.5% for twins, 26.8% for triplets and 30% for quadruplets. In vitro fertilization, use of ovulation induction agents, and cesarean delivery in the women with triplet and quadruplet were significantly higher than in those with twin pregnancies, (P = 0.0001). The mean age of mothers with triplets and quadruplets was significantly higher than with twins (P = 0.026). There was not a significant difference in respiratory and non-respiratory short outcomes between triplets, quadruplets and twins when matched for gestational age. Apgar score at 1 and 5 minutes was significantly lower in triplets and quadruplets than twins. There was no influence of birth order on neonatal mortality of triplet pregnancy. Neonatal mortality of triplet births was significantly decreased over the 5 years of the study period. CONCLUSIONS: Triplets and quadruplets have a similar neonatal outcome as twins when matched for gestational age. There is no influence of birth on the neonatal mortality of triplet pregnancy. It appears that outcome is mainly dependent on gestational age.

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Grand multifetal pregnancies (4 or more), usually caused by ovulation induction agents and assisted reproductive technologies, challenge all members of a perinatal team and put mothers and infants increased risk. Important anesthetic considerations include greater incidence of complications that in the singleton pregnancy, risks related to the large pregnant uterus, impaired uterine contraction prior to delivery secondary to fetal oxygenation, and preparation of sufficient man-power and instruments. The importance of neonatal resuscitation cannot be overemphasized. We report a successful general anesthetic management for an emergent quadruplet cesarean section at 31 weeks 5 days weeks gestational age.

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