Fertility preservation is a novel clinical discipline aiming to protect the fertility potential of young adults and children at risk of infertility. The field is evolving quickly, enriched by advances in assisted reproductive technologies and cryopreservation methods, in addition to surgical developments. The best-characterized target group for fertility preservation is the patient population diagnosed with cancer at a young age since the bulk of the data indicates that the gonadotoxicity inherent to most cancer treatments induces iatrogenic infertility. Since improvements in cancer therapy have resulted in increasing numbers of long-term survivors, survivorship issues and the negative impact of infertility on the quality of life have come to the front line. These facts are reflected in an increasing number of scientific publications referring to clinical medicine and research in the field of fertility preservation. Cryopreservation of gametes, embryos, and gonadal tissue has achieved quality standards for clinical use, with the retrieval of gonadal tissue for cryopreservation being currently the only method feasible in prepubertal children. Additionally, the indications for fertility preservation beyond cancer are also increasing since a number of benign diseases and chronic conditions either require gonadotoxic treatments or are associated with premature follicle depletion. There are many remaining challenges, and current research encompasses clinical health care and caring sciences, ethics, societal, epidemiological, experimental studies, etc.

Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non-oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH-associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants). All children had normal growth and no sign of chondrodysplasia at birth and prior to their primary disease. After HSCT, all children developed growth failure, with standard deviation scores for height at or below -3. Radiographically, all children had changes in the spine, metaphyses and epiphyses, compatible with a spondyloepimetaphyseal dysplasia. Genomic sequencing failed to detect pathogenic variants in genes associated with osteochondrodysplasias. We propose that such chondrodysplasia with growth failure is a novel, rare, but clinically important complication following early HSCT for non-oncologic pediatric diseases. The pathogenesis is unknown but could possibly involve loss or perturbation of the cartilage-bone stem cell population.

BACKGROUND:Hematological stem cell transplantation (HSCT) is an established method which has markedly increased the survival rate of hematologic malignancies since its introduction in the 1980's. The conditioning for HSCT has known gonadotoxic effects and often leads to premature loss of fertility. In this study we have prospectively followed a cohort of girls undergoing HSCT and studied the outcomes of fertility preservation treatments performed before or after HSCT, as well as the long-term reproductive outcome.METHODS:In this one-center prospective study, 39 girls counselled for fertility preservation prior to or after conditioning for HSCT for malignant or benign diseases at childhood or adolescence between 1990 and 2017 were included. The patients were presented with the option to undergo cryopreservation of ovarian tissue or oocytes depending on their age and the time available. Follicle counts of the ovarian tissue and number of oocytes collected before or after HSCT were compared between patients treated for benign and malignant diseases. Hormone measurements post HSCT treatment, including FSH and AMH, reproductive outcomes and overall survival until January 2021 were investigated.RESULTS:In total, 34 girls and adolescents underwent fertility preservation before or after HSCT. Before HSCT, ovarian tissue was cryopreserved in 15 patients and two patients had oocytes preserved. Thirteen patients cryopreserved ovarian tissue after HSCT and seven patients returned to cryopreserve oocytes. Follicles were present in all tissue samples collected prior to HSCT, and in more than half of the samples collected post-HSCT. Half of the patients had spontaneous menarche or resumed menstruation post HSCT. Overall, 35 patients had survived at end of follow up and 7 patients had achieved parenthood.CONCLUSIONS:Since fertility loss is common following HSCT, fertility preservation should be offered to all patients. Fertility preservation treatments can be performed both before and after HSCT.CLINICAL TRIAL REGISTRATION:https://clinicaltrials.gov/show/NCT04602962, identifier NTC04602962.

Options for fertility preservation (FP) through cryopreservation methods are currently available for young adults, adolescents, and children. Guidelines for FP have been provided by international clinical societies, and emergency procedures aimed at FP have been implemented into clinical practice worldwide. In this article, we review the current data on clinical standards of emergency FP in patients who are facing gonadotoxic effects of cancer treatment, and we also describe the methods that are still under development, usually denoted as experimental. In Sweden, programmes for FP have been established at large university hospitals, thus covering the whole country. The Swedish publicly financed health care covers both assisted reproduction for treatment of infertility and the cryopreservation of gametes or gonadal tissue when there is a medical indication, such as the risk to become infertile due to oncologic treatment; hence the access to FP is ensured for the whole population. At our centre at Karolinska University Hospital in Stockholm, methods for FP have been offered since 1988. In this article, we also review the oncologic indications for FP in our patient cohort of >3000 individuals during the period 1988–2018.

Background Few studies have reported the long-term outcomes of prepubertal and pubertal boys undergoing testicular biopsy for fertility preservation (FP). Procedure This prospective longitudinal study examined 21 boys (aged 1.5-14.5 years) who underwent testicular biopsy for FP prior to allogeneic (n = 20) or autologous (n = 1) hematological stem cell transplantation (HSCT) between 2003 and 2010. During counseling, pubertal boys were encouraged to produce a sperm sample by masturbation , while prepubertal boys were presented with surgical testicular tissue retrieval as an option for experimental FP. Clinical outcomes included postoperative complications, pubertal development, and sex-hormone levels. Survivors approaching adulthood were encouraged to provide semen samples. Results Twenty boys, including 14 in prepuberty and six in early puberty (Tanner stage 2-3), underwent open testicular biopsies. Two pubertal biopsies contained mature sperms, which were cryopreserved. Testicular tissue was vitrified in the remaining 18 cases. One pubertal boy (Tanner stage 4) underwent percutaneous testicular sperm aspiration and sperms obtained were cryopreserved. Postoperative complications (hematoma or infection) were rare. Overall, 14 boys survived >5 years (mean follow-up after HSCT, 7.2 years) and 11 showed advanced puberty. Semen samples were provided by five boys and obtained sperm were cryopreserved from two. Individuals at adulthood had normal testosterone levels but subnormal testicular size, high follicle stimulating hormone, and low inhibin B and anti-Mullerian hormone levels. Conclusion No long-term risks were detected during continuous clinical follow-up. Experimental testicular biopsies for FP were well accepted by the patients and families, despite the absence of methods to use prepubertal tissue for fertility treatment.

Options for fertility preservation (FP) through cryopreservation methods are currently available for young adults, adolescents, and children. Guidelines for FP have been provided by international clinical societies, and emergency procedures aimed at FP have been implemented into clinical practice worldwide. In this article, we review the current data on clinical standards of emergency FP in patients who are facing gonadotoxic effects of cancer treatment, and we also describe the methods that are still under development, usually denoted as experimental. In Sweden, programmes for FP have been established at large university hospitals, thus covering the whole country. The Swedish publicly financed health care covers both assisted reproduction for treatment of infertility and the cryopreservation of gametes or gonadal tissue when there is a medical indication, such as the risk to become infertile due to oncologic treatment; hence the access to FP is ensured for the whole population. At our centre at Karolinska University Hospital in Stockholm, methods for FP have been offered since 1988. In this article, we also review the oncologic indications for FP in our patient cohort of >3000 individuals during the period 1988-2018.

Introduction In Scandinavian countries, programs for fertility preservation are offered free of charge at tertiary-care university hospitals to all patients facing treatments with risk of subsequent sterility. In this prospective study we aimed to investigate trends in female patients' choices after counseling and fertility preservation outcomes during follow up in relation to benign vs malignant indications. Material and methods Data on 1254 females including 1076 adults and 178 girls who received fertility preservation counseling for either oncologic (n = 852) or benign indications (n = 402) at Karolinska University Hospital, Stockholm, between 1 October 1998 and 1 December 2018 were analyzed. As appropriate, t tests and chi-square tests were used to compare groups. Logistic regression was used to compare outcomes among groups depending on indications. Results Adult women generally elected to undergo oocyte retrieval after controlled ovarian stimulation for cryopreservation of embryos or oocytes (n = 538, 73%), whereas a minor proportion opted for cryopreservation of ovarian tissue retrieved through laparoscopy (n = 221, 27%). More than half of the women with a partner chose either not to fertilize their oocytes aiming at cryopreservation of oocytes or to share obtained oocytes attempting both cryopreservation of oocytes and cryopreservation of embryos. All pre-pubertal (n = 48) and 73% of post-pubertal girls (n = 66) elected cryopreservation of ovarian tissue. In recent years, an increasing number of teenagers have opted for controlled ovarian stimulation aiming at cryopreservation of oocytes, either before (n = 24, 17%) or after completion of cancer treatment (n = 15, 10%). During follow up, 27% of the women returned for a new reproductive counseling, additional fertility preservation or to attempt pregnancy. Utilization rates among individuals who were alive and of childbearing age by December 2018 indicated 29%, 8% and 5% for embryos, oocytes and ovarian tissue with live birth rates of 54%, 46% and 7%, respectively. Women with benign indications were significantly younger than women with previous malignant indications at the time of attempting pregnancy. Although the pregnancy rates were similar among both groups, the live birth rate was significantly higher in women with benign vs previous malignant indications (47% vs 21%, P = .002). Conclusions Trends in fertility preservation choices have changed over time. Women with previous malignancy had lower live birth rates than women with benign fertility preservation indications.

Sir, Despite several evidence-based guidelines available to promote fertility preservation (FP) for young patients and children, young patients still report FP as one of the top five unmet needs during their cancer care.1 Surveys have identified barriers that limit patients' access to FP, including organization-related barriers, such as lack of inter-professional cooperation, unclear referral paths for FP and the cost of the procedures.2-4 Organizational issues are particularly a problem for young female patients, who may retain fertility potential after cancer treatment during childhood but have a high risk of developing premature ovarian failure once they reach adulthood. When transitioning from childhood care to adult healthcare, routines for surveillance of infertility risks are lacking. An organization for surveillance of ovarian function is needed to give these patients the opportunity to preserve their fertility before an early menopause. Additionally, although a high proportion of practicing pediatric oncologists recognizes that it is their responsibility to discuss possible fertility impairment following treatment, they also acknowledge low confidence in their knowledge about FP methods.5 In Sweden, all university hospitals covering large regions/counties have developed programs for FP. Currently established FP strategies, including the cryopreservation of sperms, oocytes or embryos,6 are offered free of charge to patients, when indicated for medical reasons, within the tax-funded healthcare system. Previous research has evidenced inequalities in cancer patients' access to counseling and FP despite this healthcare platform.7 Methods that are still considered experimental or under development for FP of children, such as the cryopreservation of ovarian tissue and the cryopreservation of pre-pubertal testicular tissue,6, 8 are restricted to centers that have Ethics Review Board-approved research protocols. To ensure that healthcare providers become familiar with the methods for FP options and that these could be offered to patients in Sweden regardless of their residence, the Swedish Association of Local Authorities and Regions requested national guidelines. A multidisciplinary working group including specialists in reproductive medicine, pediatric oncology, pediatric endocrinology, andrology and assisted reproductive technologies from the Swedish University Hospitals was set up in 2012. The work was summarized in a comprehensive document that describes the group of patients that should be offered FP due to a substantial risk of infertility following cytotoxic treatment of cancer during childhood and adolescence, and the available methods. The guidelines are in line with international recommendations, adapted to the Swedish healthcare system, and intended to be supportive to healthcare personnel in facilitating discussions about FP with pediatric cancer patients and their guardians/relatives. The final recommendations highlight the importance of providing complete and accurate information on the current methods for FP but also their limitations, as well as the provision of information on alternative routes to becoming a parent in the future, such as gamete donation and adoption. Fertility-related information should be provided by healthcare personnel with training in that field. Supportive care by a psychologist or counselor is recommended to assist patients and their families in decision-making. The guidelines also specifically recommend that fertility counseling is offered to evaluate opportunities for undergoing FP after completion of cancer treatment, whenever FP was not possible or performed before the initiation of cancer treatment. This often occurs due to the frequent need to start treatment immediately and/or at a very young age. One suggested time-point for check up is when the children complete their follow up at the pediatric clinic when reaching adult age and are referred to adult healthcare services. Since 2016, the follow up of patients treated for childhood cancer has been standardized through a healthcare program in Sweden.9 After completion, the guidelines were submitted on a cycle of referrals to: academic associations for pediatrics, oncology, endocrinology and reproductive medicine in Sweden; the head and responsible clinician for each of Sweden's pediatric oncology centers; local and county authorities for healthcare provision; pediatric oncology nurses; the Swedish Ethical Council; patient associations; and stakeholders. After approval, the document was made public on the Swedish Human Tissue Authority's website in 2015 (www.vavnad.se).10 The working group recognized the need to periodically update the guidelines in the future, according to relevant advances in reproductive medicine and research. Booklets to provide age-adapted patient information to young children or older adolescents were also created, and these have been available online since November 2017 in Swedish, English, Finnish, Spanish and Arabic. Videos for teenagers explaining reproductive biological facts, the negative impact of cancer treatment on fertility and the available methods for FP are also available on the website (see Supporting Information Appendix S1). The UNGA network meetings for production of the Swedish guidelines were supported by the Swedish Association of Local Authorities and Regions, SALAR (Sveriges Kommuner och Landsting, SKL). This work was supported by research grants from Stockholm County Council and Karolinska Institutet, the Swedish Childhood Cancer Foundation and the Swedish Cancer Society to K.R.-W. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

In Scandinavian countries, programs for fertility preservation are offered free of charge at tertiary-care university hospitals to all patients facing treatments with risk of subsequent sterility. In this prospective study we aimed to investigate trends in female patients’ choices after counseling and fertility preservation outcomes during follow up in relation to benign vs malignant indications. Data on 1254 females including 1076 adults and 178 girls who received fertility preservation counseling for either oncologic (n = 852) or benign indications (n = 402) at Karolinska University Hospital, Stockholm, between 1 October 1998 and 1 December 2018 were analyzed. As appropriate, t tests and chi-square tests were used to compare groups. Logistic regression was used to compare outcomes among groups depending on indications. Adult women generally elected to undergo oocyte retrieval after controlled ovarian stimulation for cryopreservation of embryos or oocytes (n = 538, 73%), whereas a minor proportion opted for cryopreservation of ovarian tissue retrieved through laparoscopy (n = 221, 27%). More than half of the women with a partner chose either not to fertilize their oocytes aiming at cryopreservation of oocytes or to share obtained oocytes attempting both cryopreservation of oocytes and cryopreservation of embryos. All pre-pubertal (n = 48) and 73% of post-pubertal girls (n = 66) elected cryopreservation of ovarian tissue. In recent years, an increasing number of teenagers have opted for controlled ovarian stimulation aiming at cryopreservation of oocytes, either before (n = 24, 17%) or after completion of cancer treatment (n = 15, 10%). During follow up, 27% of the women returned for a new reproductive counseling, additional fertility preservation or to attempt pregnancy. Utilization rates among individuals who were alive and of childbearing age by December 2018 indicated 29%, 8% and 5% for embryos, oocytes and ovarian tissue with live birth rates of 54%, 46% and 7%, respectively. Women with benign indications were significantly younger than women with previous malignant indications at the time of attempting pregnancy. Although the pregnancy rates were similar among both groups, the live birth rate was significantly higher in women with benign vs previous malignant indications (47% vs 21%, P  =   .002). Trends in fertility preservation choices have changed over time. Women with previous malignancy had lower live birth rates than women with benign fertility preservation indications.

Context: Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited.Objective: To examine cancer risks in relation to GH treatment.Design: Cohort study.Setting: Population-based.Patients: Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics.Main Outcome Measures: Cancer incidence and cancer mortality.Results: Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer).Conclusions: Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation.

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Background: The long-term safety of growth hormone treatment is uncertain. Raised risks of death and certain cancers have been reported inconsistently, based on limited data or short-term follow-up by pharmaceutical companies. Patients and Methods: The SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study assembled cohorts of patients treated in childhood with recombinant human growth hormone (r-hGH) in 8 European countries since the first use of this treatment in 1984 and followed them for cause-specific mortality and cancer incidence. Expected rates were obtained from national and local general population data. The cohort consisted of 24,232 patients, most commonly treated for isolated growth failure (53%), Turner syndrome (13%) and growth hormone deficiency linked to neoplasia (12%). This paper describes in detail the study design, methods and data collection and discusses the strengths, biases and weaknesses consequent on this. Conclusion: The SAGhE cohort is the largest and longest follow-up cohort study of growth hormone-treated patients with follow-up and analysis independent of industry. It forms a major resource for investigating cancer and mortality risks in r-hGH patients. The interpretation of SAGhE results, however, will need to take account of the methods of cohort assembly and follow-up in each country.

9582 Background: Options for fertility preservation (FP) among adults and children are currently available for female and male individuals of all ages. In Sweden, publicly financed health care covers assisted reproduction and freezing of gametes and tissues for medical reasons. Methods: We reviewed clinical data of 1001 cancer patients enrolled in the FP programme at Karolinska University Hospital, Sweden, between 1998 and 2013. Results: This cohort included 945 adults and 56 children. By the time of this report, 95% of women, 90% of men and 77% of children are in the survival cohort. Most common cancer diagnoses were breast cancer, testicular cancer and lymphoma in adults, and leukemia in children.Women and children were counseled by gynecologists and pediatricians. Adult males were counseled by oncologists. All patients had access to FP options within a few days. Female patients (N=478) were offered cryopreservation of embryos, non-fertilized oocytes or pieces of ovarian cortical tissue. Males (N=523) were offered sperm freezing and cryopreservation of adult or pre-pubertal testicular tissue. Nearly one-third of survivors have returned for fertility counseling and treatment. Transfer of frozen-thawed embryos and use of frozen sperm in fertility treatments had resulted in births in over 50% of cases; in vitro fertilization of frozen-thawed oocytes resulted in transfer of embryos, but not in pregnancies. Ovarian function resumed in three women after transplantation of thawed ovarian tissue, with one pregnancy achieved. No signs of cancer recurrence related to the transplantation of ovarian tissue were observed. Five girls, prepubertal at the time of cancer treatment, underwent additionally ovarian stimulation after puberty, and mature eggs were frozen for the future. Conclusions: The utilization rates of cryo-stored gametes and embryos in this cohort are higher than those reported earlier. Although our results are encouraging, the efficacy of FP procedures can only be estimated in the group of cancer survivors who came back for fertility treatment. We have offered counseling and FP within the publicly financed health care. This may not be possible in all countries.

BackgroundTesticular dysfunction and infertility are of major concern in long‐term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). This study assesses predictive factors for very long‐term testicular recovery after allogeneic HSCT in childhood and adolescence.ProcedureTesticular volume, sperm production and long‐term need of testosterone substitution were evaluated among 106 male survivors transplanted at Huddinge and Helsinki University Hospitals from 1978 through 2000, at a mean age of 8 ± 4.6 years (range 1–17). A mean ± SD of 13 ± 4.8 years (range 4–28) had elapsed since their HSCT and the mean age of the participants was 22 ± 6.0 years (range 12–42). An adult testicular volume was recorded in 74 patients at a mean age of 19 ± 3.3 years (range 14–36).ResultsRecipients conditioned with busulfan‐based regimens or regimens containing only cyclophosphamide had significantly larger adult testicular volumes (mean volume 18 ml and 16 ml vs. 9 ml, P < 0.00001, respectively) and lower serum levels of FSH (mean 9 IU and 5 IU vs. 19 IU, P < 0.01 and 0.001, respectively) compared to those conditioned with total body irradiation (TBI). Multivariate analysis demonstrated that a non‐leukemia diagnosis (P < 0.01) and adult testicular volume ≥15 ml (P < 0.03) positively impacted spermatogenetic recovery.ConclusionsA larger adult testicular volume, normal serum levels of FSH and spermatozoa detected in a majority of seminal fluids after busulfan‐based or cyclophosphamide conditionings suggest very long‐term recovery of spermatogenesis after chemotherapy‐based regimens. A simple measurement of adult testicular volume may help predict spermatogenetic potential among pediatric HSCT survivors. Pediatr Blood Cancer 2014;61:1094–1100. © 2014 Wiley Periodicals, Inc.

Context: The long-term mortality in adults treated with recombinant GH during childhood has been poorly investigated. Recently released data from the French part of the European Union Safety and Appropriateness of GH treatments in Europe (EU SAGhE) study have raised concerns on the long-term safety of GH treatment.Objective: To report preliminary data on long-term vital status and causes of death in patients with isolated GH deficiency or idiopathic short stature or born small for gestational age treated with GH during childhood, in Belgium, The Netherlands, and Sweden.Design: Data were retrieved from national registries of GH-treated patients and vital status from National Population Registries. Causes of death were retrieved from a National Cause of Death Register (Sweden), Federal and Regional Death Registries (Belgium), or individual patient records (The Netherlands).Patients: All patients diagnosed with isolated GH deficiency or idiopathic short stature or born small for gestational age started on recombinant GH during childhood from 1985-1997 and who had attained 18 yr of age by the end of 2010 were included. Vital status was available for approximately 98% of these 2,543 patients, corresponding to 46,556 person-years of observation.Main Outcome Measure: Vital status, causes of death, age at death, year of death, duration of GH treatment, and mean GH dose during treatment were assessed.Results: Among 21 deaths identified, 12 were due to accidents, four were suicides, and one patient each died from pneumonia, endocrine dysfunction, primary cardiomyopathy, deficiency of humoral immunity, and coagulation defect.Conclusions: In these cohorts, the majority of deaths (76%) were caused by accidents or suicides. Importantly, none of the patients died from cancer or from a cardiovascular disease. (J Clin Endocrinol Metab 97: E213-E217, 2012)

Background Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller-Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller-Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes.Methods Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3.Results Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3 epsilon). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms.Conclusions The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations.