Pregnant with HIV before age 25: data from a large national study in Italy, 2001-2016.

Young pregnant women with HIV may be at significant risk of unplanned pregnancy, lower treatment coverage, and other adverse pregnancy outcomes. In a large cohort of pregnant women with HIV in Italy, among 2979 pregnancies followed in 2001-2016, 9·0% were in women <25 years, with a significant increase over time (2001-2005: 7·0%; 2006-2010: 9·1%; 2011-2016: 12·2%, P < 0·001). Younger women had a lower rate of planned pregnancy (23·2% vs. 37·7%, odds ratio (OR) 0·50, 95% confidence interval (CI) 0·36-0·69), were more frequently diagnosed with HIV in pregnancy (46·5% vs. 20·9%, OR 3·29, 95% CI 2·54-4·25), and, if already diagnosed with HIV before pregnancy, were less frequently on antiretroviral treatment at conception (<25 years: 56·3%; ⩾25 years: 69·0%, OR 0·58, 95% CI 0·41-0·81). During pregnancy, treatment coverage was almost universal in both age groups (98·5% vs. 99·3%), with no differences in rate of HIV viral suppression at third trimester and adverse pregnancy outcomes. The data show that young women represent a growing proportion of pregnant women with HIV, and are significantly more likely to have unplanned pregnancy, undiagnosed HIV infection, and lower treatment coverage at conception. During pregnancy, antiretroviral treatment, HIV suppression, and pregnancy outcomes are similar compared with older women. Earlier intervention strategies may provide additional benefits in the quality of care for women with HIV.

Immediate delivery or expectant management in gestational diabetes at term: the GINEXMAL randomised controlled trial.

OBJECTIVE: To evaluate maternal and perinatal outcomes after induction of labour versus expectant management in pregnant women with gestational diabetes at term. DESIGN: Multicentre open-label randomised controlled trial. SETTING: Eight teaching hospitals in Italy, Slovenia, and Israel. SAMPLE: Singleton pregnancy, diagnosed with gestational diabetes by the International Association of Diabetes and Pregnancy Study Groups criteria (IADPSGC), between 38+0 and 39+0 weeks of gestation, without other maternal or fetal conditions. METHODS: Patients were randomly assigned to induction of labour or expectant management and intensive follow-up. Data were analysed by 'intention to treat'. MAIN OUTCOME MEASURES: The primary outcome was incidence of caesarean section. Secondary outcomes were maternal and perinatal mortality and morbidity. RESULTS: A total of 425 women were randomised to the study groups. The incidence of caesarean section was 12.6% in the induction group versus 11.7% in the expectant group. No difference was found between the two groups (relative risk, RR 1.06; 95% confidence interval, 95% CI 0.64-1.77; P = 0.81). The incidence of non-spontaneous delivery, either by caesarean section or by operative vaginal delivery, was 21.0 and 22.3%, respectively (RR 0.94; 95% CI 0.66-1.36; P = 0.76). Neither maternal nor fetal deaths occurred. The few cases of shoulder dystocia were solved without any significant birth trauma. CONCLUSIONS: In women with gestational diabetes, without other maternal or fetal conditions, no difference was detected in birth outcomes regardless of the approach used (i.e. active versus expectant management). Although the study was underpowered, the magnitude of the between-group difference was very small and without clinical relevance. TWEETABLE ABSTRACT: Immediate delivery or expectant management in gestational diabetes at term?

Repeat partial nephrectomy for recurrence of Von Hippel-Lindau-related renal cell carcinoma in an autotransplanted kidney.

Von Hippel-Lindau disease predisposes to develop renal cell carcinoma (RCC). Treatment is frequently challenging due to presence of bilateral tumors and high risk of recurrence. We present the case of a VHL-patient with bilateral recurrence of clear-cell RCC after bilateral partial nephrectomy and autotransplantation on one side. Recurrence on the transplanted kidney was treated with repeat partial nephrectomy with good oncological and functional outcomes. This approach is feasible in centres with wide experience in partial nephrectomy and renal transplantation when minimally invasive tumor ablation is not indicated.

Gestational diabetes and fetal growth acceleration: induction of labour versus expectant management.

AIM: The aim of the study was to compare elective induction of labour at 38 weeks versus expectant management in A1 and A2 gestational diabetes (GDM) pregnancies with fetal growth acceleration. Primary outcome of the study was C-section (CS) rate, while secondary outcomes were macrosomia incidence and adverse perinatal outcomes. METHODS: A retrospective cohort study was carried out. Data were collected between 1996 and 2006 and evaluated through patients' records analysis. Differences between the two study groups were investigated using non-parametric tests for continuous variables and χ2 test for categorical ones. RESULTS: There was no significant difference between induction and expectant management in terms of caesarean section rate. A trend favoring women in the induction group in terms of incidence of macrosomia and neonatal outcomes was identified, but results were not statistically significant. CONCLUSION: Labour induction at 38 weeks in GDM patients with fetal growth acceleration does not seem to determine an increased incidence of C-section in comparison to expectant management, particularly in case of maternal obesity.

Determinants of Length of Stay After Vaginal Deliveries in the Friuli Venezia Giulia Region (North-Eastern Italy), 2005-2015.

Although length of stay (LoS) after childbirth has been diminishing in several high-income countries in recent decades, the evidence on the impact of early discharge (ED) on healthy mothers and term newborns after vaginal deliveries (VD) is still inconclusive and little is known on the characteristics of those discharged early. We conducted a population-based study in Friuli Venezia Giulia (FVG) during 2005-2015, to investigate the mean LoS and the percentage of LoS longer than our proposed ED benchmarks following VD: 2 days after spontaneous vaginal deliveries (SVD) and 3 days post instrumental vaginal deliveries (IVD). We employed a multivariable logistic as well as a linear regression model, adjusting for a considerable number of factors pertaining to health-care setting and timeframe, maternal health factors, newborn clinical factors, obstetric history factors, socio-demographic background and present obstetric conditions. Results were expressed as odds ratios (OR) and regression coefficients (RC) with 95% confidence interval (95%CI). The adjusted mean LoS was calculated by level of pregnancy risk (high vs. low). Due to a very high number of multiple tests performed we employed the procedure proposed by Benjamini-Hochberg (BH) as a further selection criterion to calculate the BH p-value for the respective estimates. During 2005-2015, the average LoS in FVG was 2.9 and 3.3 days after SVD and IVD respectively, and the pooled regional proportion of LoS > ED was 64.4% for SVD and 32.0% for IVD. The variation of LoS across calendar years was marginal for both vaginal delivery modes (VDM). The adjusted mean LoS was higher in IVD than SVD, and although a decline of LoS > ED and mean LoS over time was observed for both VDM, there was little variation of the adjusted mean LoS by nationality of the woman and by level of pregnancy risk (high vs. low). By contrast, the adjusted figures for hospitals with shortest (centres A and G) and longest (centre B) mean LoS  were 2.3 and 3.4 days respectively, among "low risk" pregnancies. The corresponding figures for "high risk" pregnancies were 2.5 days for centre A/G and 3.6 days for centre B. Therefore, the shift from "low" to "high" risk pregnancies in all three latter centres (A, B and G) increased the mean adjusted LoS just by 0.2 days. By contrast, the discrepancy between maternity centres with highest and lowest adjusted mean LoS post SVD (hospital B vs. A/G) was 1.1 days both among "low risk" (1.1 = 3.4-2.3 days) and "high risk" (1.1 = 3.6-2.5) pregnanices. Similar patterns were obseved also for IVD. Our adjusted regression models confirmed that maternity centres were the main explanatory factor for LoS after childbirth in both VDM. Therefore, health and clinical factors were less influential than practice patterns in determining LoS after VD. Hospitalization and discharge policies following childbirth in FVG should follow standardized guidelines, to be enforced at hospital level. Any prolonged LoS post VD (LoS > ED) should be reviewed and audited if need be. Primary care services within the catchment areas of the maternity centres of FVG should be improved to implement the follow up of puerperae undergoing ED after VD.

Determinants of length of stay after cesarean sections in the Friuli Venezia Giulia Region (North-Eastern Italy), 2005-2015.

Since Italy has the highest cesarean section (CS) rate (38.1%) among all European countries, the containment of health care costs associated with CS is needed, along with control of length of hospital stay (LOS) following CS. This population based cross-sectional study aims to investigate LoS post CS (overall CS, OCS; planned CS, PCS; urgent/emergency CS, UCS), in Friuli Venezia Giulia (a region of North-Eastern Italy) during 2005-2015, adjusting for a considerable number factors, including various obstetric conditions/complications. Maternal and newborn characteristics (health care setting and timeframe; maternal health factors; child's size factors; child's fragility factors; socio-demographic background; obstetric history; obstetric conditions) were used as independent variables. LoS (post OCS, PCS, UCS) was the outcome measure. The statistical analysis was conducted with multivariable linear (LoS expressed as adjusted mean, in days) as well as logistic (adjusted proportion of LoS > 4 days vs. LoS ≤ 4 days, using a 4 day cutoff for early discharge, ED) regression. An important decreasing trend over time in mean LoS and LoS > ED was observed for both PCS and UCS. LoS post CS was shorter with parity and history of CS, whereas it was longer among non-EU mothers. Several obstetric conditions/complications were associated with extended LoS. Whilst eclampsia/pre-eclampsia and preterm gestations (33-36 weeks) were predominantly associated with longer LoS post UCS, for PCS LoS was significantly longer with birthweight 2.0-2.5 kg, multiple birth and increasing maternal age. Strong significant inter-hospital variation remained after adjustment for the major clinical conditions. This study shows that routinely collected administrative data provide useful information for health planning and monitoring, identifying inter-hospital differences that could be targeted by policy interventions aimed at improving the efficiency of obstetric care. The important decreasing trend over time of LoS post CS, coupled with the impact of some socio-demographic and obstetric history factors on LoS, seemingly suggests a positive approach of health care providers of FVG in decision making on hospitalization length post CS. However, the significant role of several obstetric conditions did not influence hospital variation. Inter-hospital variations of LoS could depend on a number of factors, including the capacity to discharge patients into the surrounding non-acute facilities. Further studies are warranted to ascertain whether LoS can be attributed to hospital efficiency rather than the characteristics of the hospital catchment area.

Understanding Factors Leading to Primary Cesarean Section and Vaginal Birth After Cesarean Delivery in the Friuli-Venezia Giulia Region (North-Eastern Italy), 2005-2015.

Although there is no evidence that elevated rates of cesarean sections (CS) translate into reduced maternal/child perinatal morbidity or mortality, CS have been increasingly overused almost everywhere, both in high and low-income countries. The primary cesarean section (PCS) has become a major driver of the overall CS (OCS) rate, since it carries intrinsic risk of repeat CS (RCS) in future pregnancies. In our study we examined patterns of PCS, pl compared with planned TOLAC anned PCS (PPCS), vaginal birth after 1 previous CS (VBAC-1) and associated factors in Friuli Venezia Giulia (FVG), a region of North-Eastern Italy, collecting data from its 11 maternity centres (coded from A to K) during 2005-2015. By fitting three multiple logistic regression models (one for each delivery mode), we calculated the adjusted rates of PCS and PPCS among women without history of CS, whilst the calculation of the VBAC rate was restricted to women with just one previous CS (VBAC-1). Results, expressed as odds ratio (OR) with 95% confidence interval (95%CI), were controlled for the effect of hospital, calendar year as well as several factors related to the clinical and obstetric conditions of the mothers and the newborn, the obstetric history and socio-demographic background. In FVG during 2005-2015 there were 24,467 OCS (rate of 24.2%), 19,565 PCS (19.6%), 7,736 PPCS (7.7%) and 2,303 VBAC-1 (28.4%). We found high variability of delivery mode (DM) at hospital level, especially for PCS and PPCS. Breech presentation was the strongest determinant for PCS as well as PPCS. Leaving aside placenta previa/abuptio placenta/ante-partum hemorrhage, further significant factors, more importantly associated with PCS than PPCS were non-reassuring fetal status and obstructed labour, followed by (in order of statistical significance): multiple birth; eclampsia/pre-eclampsia; maternal age 40-44 years; placental weight 600-99 g; oligohydramios; pre-delivery LoS 3-5 days; maternal age 35-39 years; placenta weight 1,000-1,500 g; birthweight < 2,000 g; maternal age ≥ 45 years; pre-delivery LoS ≥ 6 days; mother's age 30-34 years; low birthweight (2,000-2,500 g); polyhydramnions; cord prolaspe; ≥6 US scas performed during pregnancy and pre-term gestations (33-36 weeks). Significant factors for PPCS were (in order of statistical significance): breech presentation; placenta previa/abruptio placenta/ante-partum haemorrhage; multiple birth; pre-delivery LoS ≥ 3 days; placental weight ≥ 600 g; maternal age  40-44 years; ≥6 US scans performed in pregnancy; maternal age ≥ 45 and 35-39 years; oligohydramnios; eclampsia/pre-eclampsia; mother's age 30-34 years; birthweight <2,000 g; polyhydramnios and pre-term gestation (33-36 weeks). VBAC-1 were more likely with gestation ≥ 41 weeks, placental weight <500 g and especially labour analgesia. During 2005-2015 the overall rate of PCS in FVG (19.6%) was substantially lower than the corresponding figure reported in 2010 for the entire Italy (29%) and still slightly under the most recent national PCS rate for 2017 (22.2%). The VBAC-1 rate on women with history of one previous CS in FVG was 28.4% (25.3% considering VBAC on all women with at least 1 previous CS), roughly three times the Italian national rate of 9% reported for 2017. The discrepancy between the OCS rate at country level (38.1%) and FVG's (24.2%) is therefore mainly attributable to RCS. Although there was a marginal decrease of PCS and PPCS crudes rates over time in the whole region, accompained by a progressive enhancement of the crude VBAC rate, we found remarkable variability of DM across hospitals. To further contain the number of unnecessary PCS and promote VBAC where appropriate, standardized obstetric protocols should be introduced and enforced at hospital level. Decision-making on PCS should be carefully scrutinized, introducing a diagnostic second opinion for all PCS, particularly for term singleton pregancies with cephalic presentation and in case of obstructed labour as well as non-reassuring fetal status, grey areas potentially affected by subjective clinical assessment. This process of change could be facilitated with education of staff/patients by opinion leaders and prenatal counseling for women and partners, although clinical audits, financial penalties and rewards to efficient maternity centres could also be considered.

Gestational diabetes mellitus: Prevention, diagnosis and treatment. A fresh look to a busy corner.

BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy complication characterized by hyperglycaemia with onset or first recognition during pregnancy. Risk factors include family history of diabetes, previous GDM, genetic predisposition for GDM/type 2 diabetes, insulin resistance conditions such as overweight, obesity and ethnicity. Women with GDM are at high risk for fetal macrosomia, small for gestational age, neonatal hypoglycaemia, operative delivery and caesarean delivery. The aim of this narrative review is to summarize the most recent findings of diagnosis and treatment of GDM in order to underline the importance to promote adequate prevention of this disease, especially through lifestyle interventions such as diet and physical activity. METHODS: The research was conducted using the following electronic databases, MEDLINE, EMBASE, Web of Science, Scopus, ClinicalTrial.gov, OVID and Cochrane Library, including all published randomized and non-randomized studies as well as narrative and systematic reviews. RESULTS: The lack of universally accepted criteria makes the definition of diagnosis and prognosis of this condition difficult. Early diagnosis and glucose blood level control may improve maternal and fetal short and long-term outcomes. Treatment strategies include nutritional interventions and exercise. Medical treatment can be necessary if these strategies are not effective. Moreover, novel non-pharmacologic agents such as myo-inositol seem to be effective and safe both in the prevention and the treatment of GDM. CONCLUSIONS: It is important to promote adequate prevention of GDM. Further studies are needed in order to better define the most appropriate strategies for the clinical management of women affected by GDM.

Age-dependent effects of moderate differences in environmental predictability forecasted by climate change, experimental evidence from a short-lived lizard (Zootoca vivipara).

Whether and how differences in environmental predictability affect life-history traits is controversial and may depend on mean environmental conditions. Solid evidence for effects of environmental predictability are lacking and thus, the consequences of the currently observed and forecasted climate-change induced reduction of precipitation predictability are largely unknown. Here we experimentally tested whether and how changes in the predictability of precipitation affect growth, reproduction, and survival of common lizard Zootoca vivipara. Precipitation predictability affected all three age classes. While adults were able to compensate the treatment effects, yearlings and juvenile females were not able to compensate negative effects of less predictable precipitation on growth and body condition, respectively. Differences among the age-classes' response reflect differences (among age-classes) in the sensitivity to environmental predictability. Moreover, effects of environmental predictability depended on mean environmental conditions. This indicates that integrating differences in environmental sensitivity, and changes in averages and the predictability of climatic variables will be key to understand whether species are able to cope with the current climatic change.

[Pregnancy in HIV-positive women: 6 years of activity of the Regional Reference Center]. / La gravidanza in donna HIV positiva: 6 anni di attività del Centro di Riferimento Regionale.

AIM: With this study, we wanted to evaluate HIV-positive pregnant mothers followed at the HIV Reference Center of Friuli Venezia Giulia and to describe obstetric treatment aimed at identifying vertical transmission factors and at undertaking a correct diagnostic-therapeutic approach to this patient group. The data include a large case series from the European Collaborative Study on HIV in Pregnancy, in which our facility is a collaborating center. METHODS: The protocol includes the administration of personalized antiretroviral therapy to seropositive patients at the first visit. An elective caesarean section is performed at 38 weeks gestation. Antiretroviral therapy is continued in the neonate. Breastfeeding is prohibited. RESULTS: From 1998 to 2002, 28 pregnant mothers with HIV infection were followed. Most patients came from out of region and had acquired the infection through heterosexual intercourse with a serodiscordant partner. In 1 in 3 patients, a diagnosis of seropositivity was made during pregnancy. One case of vertical transmission was observed. CONCLUSIONS: When appropriate prevention measures are instituted, the percentage of vertical transmission of infection can be reduced to less than 1% in Europe today. An important part of this effort is early screening for HIV infection in pregnancy. Other fundamental measures are the institution of antiretroviral therapy starting from the first weeks of pregnancy, monitoring of pregnancy at a tertiary reference center, intravenous administration of therapies before caesarean section, possibly not during labor and with the membrane intact. Equally important factors are neonatal therapy, adequate pediatric monitoring after the infant is born and discontinuation of breastfeeding.

Intrapartum fetal heart rate monitoring interpretation in labour: a critical appraisal.

Electronic fetal monitoring (EFM) has been introduced in the obstetrics practice as a test to identify the first signs of fetal deterioration, allowing a prompt intervention to reduce neonatal morbidity and mortality. However, results from clinical trials fail to demonstrate a clear benefit with the use of EFM. No decrease in the incidence of cerebral palsy due to intrapartum asphyxia has been achieved and a significant increase in the rate of operative deliveries and in medico-legal litigations has been observed instead. Despite the lack of evidence supporting its safety and effectiveness, this method is routinely used in the clinical practice and periodical updated guidelines to standardize the method of interpretation and proper actions are proposed. However, limitations still exist and the unavoidable consequences are the increasing rate of caesarean delivery, partly due to a defensive attitude in medical choices, and medico-legal litigations for presumed inappropriate evaluation in case of perinatal adverse event. While Obstetrics Societies are trying to "fight" the rise in caesarean section rates, intrapartum EFM tracings are taken in the court proceedings as one of the main evidences in case of adverse event. The aim of this review is to discuss the limitations of guidelines dealing with intrapartum EFM and the pathophysiological basis to assess the suspicious tracings which represent the most observed and critical issue of EFM interpretation.

Detection of antigenic determinants in the Treponema pallidum membrane protein TmpA using overlapping synthetic peptides.

The antigenic structure of the 42 kDa membrane protein of Treponema Pallidum, TmpA, was studied using synthetic peptides. Ten overlapping peptides, 35-40 residues each, were synthesized in order to cover the entire sequence of the molecule. The antigenic activity of the fragments was examined by enzyme-linked immunosorbent assay (ELISA). In this way it was possible to demonstrate a significant antigenic activity of four peptides which were reactive with syphilitic sera. The N-terminal fragment TmpA1, 38 residues long, proved to be the most reactive. Its antigenic structure was therefore studied in more detail, by examining shorter fragments. The N-terminal portion of TmpA1, consisting of 19 residues, (ASGAKEEAEKKAAEQRALL) represents an important fragment of the molecule, and was specifically interactive with most of the syphilitic sera examined.

The value of ultrasound screening for proximal vein thrombosis after total hip arthroplasty--a prospective cohort study.

The role of ultrasound screening for proximal deep-vein thrombosis (DVT) following major hip surgery is controversial. 202 consecutive patients, who had received warfarin prophylaxis after total hip arthroplasty underwent a bilateral ultrasound assessment of the proximal vein system (using the criterion of vein compressibility) before hospital discharge. In the 9 patients (4.5%; 95% CI, 2.1-8.3%) with positive test anticoagulant treatment was successfully continued for three months. In all the remaining 193 patients the warfarin treatment was withdrawn. A second ultrasound test was performed 15 days later, and showed a new (asymptomatic) abnormality compatible with proximal DVT in 2 patients (1.0%; 95% CI, 0.1-3.7%). All other 191 patients remained asymptomatic until the completion of a 3-month follow-up period (rate of symptomatic thromboembolism, 0/191, 0%; 95% CI, 0-1.9%). Because of the relatively high incidence of proximal DVT in patients undergoing major orthopaedic surgery under warfarin prophylaxis, screening for proximal DVT at hospital discharge in these patients is indicated. The negativity of this test has the potential of safely preventing the extension of anticoagulation beyond hospital stay. A larger controlled study in which the value of this strategy is tested against the prolongation of oral anticoagulation in patients with a negative ultrasound screening at discharge is indicated.

Synthesis and physicochemical characterization of a new material (PUPA) based on polyurethane and poly(amido-amine) components capable of strongly adsorbing quantities of heparin.

The synthesis of new materials (PUPAs) based on a commercial polyurethane and a heparin-complexing polymer, poly(amido-amine), was studied. PUPAs are capable of adsorbing heparin because the basic nitrogens of poly(amido-amine), once protonated, interact with the negative charges carried by the heparin molecule. Six different samples of PUPA were synthesized having a varied ratio of the components. The quantity of basic nitrogen on the surface and the bound heparin for each sample was determined. Two different kinds of heparin are present on a PUPA surface: one is strongly bound but can be detached by 0.1 M NaOH solution, the other is physically adsorbed and is slowly released by a stream of saline solution. A relationship between the quantity of strongly bound heparin and basic nitrogen was found. SEM and FTIR-ATR analysis were performed on all the PUPA samples. The mechanical characteristics change according to chemical composition.

A material (PUPA) presenting both the properties of polyurethanes and the capacity of adsorbing a high quantity of heparin.

Polyurethanes are widely used for biomedical applications, but there is still a constant search for improved blood-compatible materials. We studied a material (PUPA) obtained by the interconnection between a poly(amido-amine), N2LL, capable of forming stable complexes with heparin and a commercial polyurethane, Pellethane 2363-80AE, using hexamethylenediisocyanate as the crosslinking agent. The amount of absorbed heparin (evaluated by biological tests) was generally much higher than that found on the poly(amido-amine) surface-grafted polyurethane.

Fructose-induced hyperuricemia in psoriasis and psoriatic arthritis.

Acute intravenous infusion of fructose was given to 30 normal subjects and 27 normo-uricemic patients affected by psoriasis, 12 with cutaneous involvement only and 15 with psoriatic arthritis. Serum uric acid was measured before and after infusion. A significantly lower increase in serum uric acid levels was found in psoriatic patients in comparison to controls, and the increase rate appeared to be significant only in controls. Moreover, the overall fructose-induced hyperuricemia was significantly lower in the group of patients with psoriatic arthritis than in normal subjects. Since the fructose-induced increase of serum uric acid is most probably achieved by an augmented turnover of preformed purine nucleotides, it is suggested that in normouricemic patients with psoriasis the "pool" of purine nucleotides is lower than normal. Such a condition seems to be more evident in psoriatic arthritis.

[The importance and limits of laboratory tests for evaluating the transplacental passage of fetal erythrocytes into the maternal circulation]. / Importanza e limiti dei test di laboratorio per valutare il passaggio transplacentare di emazie fetali nel circolo materno.

The KBB acid elution test is used to assess the presence and extent of transplacental passage of fetal cells into the maternal circulation both as a diagnostic aid in detecting hemorrhage before birth and in monitoring pregnancies at risk for hemolytic disease of the newborn. However the technique is ineffective when an hereditary Hb-pathy with associated increase in HbF is present in the mother, like the HPFH, delta-beta thalassemia and other hereditary abnormal hemoglobins. A mother with HPFH and another mother with delta-beta thalassemia with false positive result of the acid-elution test are described and the need for an extension of the clinical and laboratory study in families with hereditary HbF disorder is stressed.