Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for mucocutaneous bleeding disorders.

BACKGROUND: Excessive or abnormal mucocutaneous bleeding (MCB) may impact all aspects of the physical and psychosocial wellbeing of those who live with it (PWMCB). The evidence base for the optimal diagnosis and management of disorders such as inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD), Ehlers-Danlos syndromes (EDS), and von Willebrand disease (VWD) remains thin with enormous potential for targeted research. RESEARCH DESIGN AND METHODS: National Hemophilia Foundation and American Thrombosis and Hemostasis Network initiated the development of a National Research Blueprint for Inherited Bleeding Disorders with extensive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. They recruited multidisciplinary expert working groups (WG) to distill community-identified priorities into concrete research questions and score their feasibility, impact, and risk. RESULTS: WG2 detailed 38 high priority research questions concerning the biology of MCB, VWD, inherited qualitative platelet function defects, HDS/EDS, HHT, bleeding disorder of unknown cause, novel therapeutics, and aging. CONCLUSIONS: Improving our understanding of the basic biology of MCB, large cohort longitudinal natural history studies, collaboration, and creative approaches to novel therapeutics will be important in maximizing the benefit of future research for the entire MCB community.

More people experience mucocutaneous bleeding (MCB), affecting tissues like skin and gums, than have hemophilia A or B. MCB is not understood as well as hemophilia. Common types of MCB include nosebleeds, bleeding gums, heavy menstrual bleeding, and digestive tract bleeding. Mucocutaneous inherited bleeding disorders include inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS), von Willebrand Disease (VWD), and others. Diagnosing and treating MCB is complicated and sometimes medical providers dismiss the bleeding that patients report when they cannot find a medical explanation for it. Many people with mucocutaneous bleeding (PWMCB) do not receive the care they need; for example, women with VWD live with symptoms for, on average, 16 years before they are diagnosed in the US. This struggle to obtain care has important negative impacts on patients' physical and psychological health and their quality-of-life. The National Hemophilia Foundation (NHF), a large US bleeding disorders patient advocacy organization, set out to develop a National Research Blueprint for Inherited Bleeding Disorders focused on community priorities. They brought together a group of patients, providers, and researchers with MCB expertise to identify the research that would most improve the lives of PWMCB through targeted and accessible diagnostics and therapies. We report in this paper that research is needed to better understand the biology of MCB and to define the mechanisms of disease in these disorders. We also describe high priority research questions for each of the main disorders, novel therapeutics, and aging.

Quality of life after mandibulectomy: the impact of the resected subsite.

The purpose of this study was to identify the factors that impact the quality of life (QOL) scores of patients undergoing mandibulectomy. All patients with a diagnosis of an oral cavity neoplasm involving the mandible who underwent a mandibulectomy between January 1, 2000 and December 31, 2015 and completed a University of Washington QOL questionnaire (UW-QOL) were included in the study. Fifty-eight patients fulfilled all inclusion criteria and completed the UW-QOL questionnaire. Forty patients (69%) underwent a segmental mandibulectomy and 18 patients underwent a marginal mandibulectomy. Forty-eight patients (82.7%) had a free flap reconstruction. There was no significant difference in the QOL scores between patients who underwent a marginal or a segmental mandibulectomy. In contrast, patients who underwent symphysial resection reported significantly worse scores in various domains compared to patients with body or ramus segmental mandibulectomy. Patients who underwent a segmental mandibulectomy that included the symphysis had worse outcomes in chewing, recreation, health-related and social QOL domains compared to those whose mandibulectomy did not include the symphysis.

[One stage combined endoscopic and per-oral buccal fat pad approach for large oro-antral-fistula closure with secondary chronic maxillary sinusitis].

There are numerous surgical approaches for oro-antral-fistula (OAF) closure. Secondary sinus disease is still considered by many experts a relative contra indication for primary closure. To describe a single-stage combined endoscopic sinus surgery and per-oral buccal fat pad (BFP) flap approach for large OAF causing chronic maxillary sinusitis. The records of all the patients with OAF and chronic manifestations of secondary rhinosinusitis that were treated between 2010 and 2013 in our tertiary care medical center were reviewed. The exclusion criteria were: OAF 5 mm, resolved sino-nasal disease, OAF secondary to malignancy, recurrent fistula, medical history that included radiotherapy to the maxillary bone and age <18 years. Each procedure was performed by a team consisting of a rhinologist and a maxillofacial surgeon. The surgical approach included an endoscopic middle antrostomy with maxillary sinus drainage, and a per-oral BFP regional flap for OAF closure. Total OAF closure, complications and need for revision surgeries. Forty-five patients that underwent OAF closure together with sinus surgery using a combined endoscopic sinus surgery (ESS) and BFP flap approach met the inclusion criteria. There were 28 males and 17 females with a mean ± SD age of 53.5 ± 14.9 years (range 22-80 years). The presenting signs and symptoms included purulent rhinorrhea (n = 22, 48.9%), foreign body in sinus (n = 10, 22.2%) nasal congestion (n = 7, 15.5%), halitosis (n = 6, 13.3%) and pain (n = 5, 12.2%). Surgical complications included local pain (n = 2, 4.4%), persistent rhinitis (n = 2, 4.4%) and synechia (n = 1, 2.2%). One patient required revision surgery due, to an unresolved OAF. The OAF of all the other 44 patients (97.8%) was closed after the first procedure and the paranasal sinuses on the treated side were completely recovered. The mean follow-up time for the group was 7.6 ± 4.3 months (7-21 months), and no untoward sequelae or recurrence were reported. Combined, one step, endoscopic Maxillary sinus drainage together with per-oral BFP flap approach is an efficacious surgical approach for safe closure of OAFs that are complicated with secondary chronic maxillary sinusitis.

Low levels of 25-hydroxyvitamin D before allogeneic hematopoietic SCT correlate with the development of chronic GVHD.

Vitamin D, a hormone involved in bone and calcium homeostasis, has been shown to have potent immunomodulatory effects. We performed a retrospective cohort analysis to evaluate whether monohydroxyvitamin D levels before allogeneic hematopoietic SCT (HSCT) correlate with the risk of GVHD. Fifty-three patients who underwent myeloablative HSCT were studied. Vitamin D levels were measured in serum samples obtained before HSCT. The median 25-hydroxyvitamin vitamin D level was 21.9 ng/mL (7.8-45.7). The cumulative incidence (CI) of grades II-IV acute GVHD at 100 days was 53.1% in patients with vitamin D<25, versus 33.3% in patients with vitamin D ≥ 25 ng/mL (P=0.13). The CI of chronic GVHD (cGVHD) at 2 years in patients with vitamin D<25 was 63.8%, compared with 23.8% in patients with vitamin D ≥ 25 ng/mL (P=0.009). Similarly, the 2 year CI of extensive cGVHD was significantly greater in patients with vitamin D<25 compared with those with vitamin D ≥ 25 ng/mL (54.5% versus 14.3%, P=0.005). In a multivariable competing risk model, low pre-transplant vitamin D levels remained a significant factor associated with cGVHD (hazard ratio=5.26, P=0.02). Our results demonstrate that vitamin D deficiency before HSCT is associated with an increased risk of cGVHD.

Correlation of cystatin-C with glomerular filtration rate by inulin clearance in pregnancy.

OBJECTIVE: To test utility of cystatin-C as a marker of glomerular filtration rate during pregnancy, we performed serial correlations with inulin clearance during pregnancy and postpartum. METHODS: Twelve subjects received inulin infusions and serum cystatin-C at three time points. Pearson's correlation coefficient was calculated. RESULTS: Cystatin-C levels ranged 0.66-1.48 mg/L during pregnancy, and 0.72-1.26 mg/L postpartum. Inulin clearance ranged 130-188 mL/min during pregnancy, and 110-167 mL/min postpartum. Cystatin-C did not correlate with inulin clearance at any time point. CONCLUSION: Serum cystatin-C did not correlate with inulin clearance during pregnancy or postpartum.

Fate of the black string instability.

Gregory and Laflamme showed that certain nonextremal black strings (and p-branes) are unstable to linearized perturbations. It is widely believed that this instability will cause the black string horizon to classically pinch off and then quantum mechanically separate, resulting in higher dimensional black holes. We argue that this cannot happen. Under very mild assumptions, classical event horizons cannot pinch off. Instead, they settle down to new static black string solutions which are not translationally invariant along the string.

Interleukin-6 differentially stimulates haptoglobin production by peritoneal and endometriotic cells in vitro: a model for endometrial-peritoneal interaction in endometriosis.

Based on our previous observation that peritoneal endometriotic (PE) lesions synthesize in vivo substantially more haptoglobin (Hp) than related eutopic tissues, we hypothesized that this increase in Hp production was due to endometrial-peritoneal interactions. As interleukin-6 (IL-6) stimulates Hp in other tissues and is produced by endometrial cells, we tested our hypothesis by evaluating the effects of IL-6 on Hp production by PE cells, normal peritoneal (P) cells, and eutopic endometrial cells from women with (UE-E) and without endometriosis (UE-C) using semiquantitative RT-PCR and enzyme-linked immunoabsorbent assay. Endogenous production of IL-6 was also assessed. Treatment with human recombinant IL-6 and dexamethasone significantly increased Hp production by P or PE cells in a dose- and time-dependent manner (P < 0.05). Hp messenger ribonucleic acid was not detected in UE-E and UE-C cells in the absence or presence of IL-6 and dexamethasone. PE and UE-E cells expressed significantly more IL-6 messenger ribonucleic acid than P and UE-C cells (P < 0.05). Moreover, UE-E cells secreted 6 times more IL-6 protein than UE-C cells (P < 0.05). These findings support our hypothesis and suggest a novel endometrial-peritoneal interaction whereby locally synthesized IL-6 and Hp may participate in the establishment and persistence of peritoneal endometriosis.

Quinolones and false-positive urine screening for opiates by immunoassay technology.

CONTEXT: Millions of assays are performed each year to monitor for substance abuse in various settings. When common medications cross-react with frequently used testing assays, false-positive results can lead to invalid conclusions. OBJECTIVE: To evaluate cross-reactivity of quinolone antimicrobials in common opiate screening assays and to assess the in vivo implications of this phenomenon. DESIGN, SETTING, AND PARTICIPANTS: The reactivity of 13 quinolones (levofloxacin, ofloxacin, pefloxacin, enoxacin, moxifloxacin, gatifloxacin, trovafloxacin, sparfloxacin, lomefloxacin, ciprofloxacin, clinafloxacin, norfloxacin, and nalidixic acid) was tested in 5 commercial opiate screening assays from September 1998 to March 1999. In 6 healthy volunteers, we confirmed the cross-reactivity of levofloxacin or ofloxacin with these opiate screening assays. MAIN OUTCOME MEASURE: Opiate assay activity (threshold for positive result, 300 ng/mL of morphine). RESULTS: Nine of the quinolones caused assay results above the threshold for a positive result in at least 1 of the assays. Four of the assay systems caused false-positive results for at least 1 quinolone. Eleven of the 13 compounds caused some opiate activity by at least 1 assay system. At least 1 compound caused opiate assay activity in all 5 assay systems. Levofloxacin, oflaxacin, and perfloxacin were most likely to lead to a false-positive opiate result. Positive results were obtained in urine from all 6 volunteers. CONCLUSION: Greater attention to the cross-reactivity of quinolones with immunoassays for opiates is needed to minimize the potential for invalid test interpretation.

Black holes radiate mainly on the brane.

We examine the evaporation of a small black hole on a brane in a world with large extra dimensions. Since the masses of many Kaluza-Klein modes are much smaller than the Hawking temperature of the black hole, it has been claimed that most of the energy is radiated into these modes. We show that this is incorrect. Most of the energy goes into the modes on the brane. This raises the possibility of observing Hawking radiation in future high energy colliders if there are large extra dimensions.

Differential expression and localization of de-novo synthesized endometriotic haptoglobin in endometrium and endometriotic lesions.

Endometriosis protein-I (ENDO-I) mRNA expression and protein localization were evaluated using in-situ hybridization and immunohistochemistry in endometriotic lesions and eutopic endometrium from women with endometriosis, and in eutopic endometrium from women without endometriosis (controls). When present, ENDO-I mRNA and protein were observed in the functionalis zone of endometrial stroma and the stroma of endometriotic lesions. Expression and localization differences were scored and statistically analysed. During the secretory stage, ENDO-I mRNA expression by endometriotic lesions and eutopic endometrium from women with disease was significantly greater than ENDO-I mRNA expression by proliferative stage eutopic endometrium from women with disease or eutopic endometrium from controls, regardless of cycle stage (P < 0.001). More ENDO-I protein was localized in endometriotic lesions and eutopic endometrium from women with disease than in eutopic endometrium from controls, regardless of cycle stage (P < 0.001). Differential expression and localization of ENDO-I may help develop minimally invasive diagnostic strategies for endometriosis. Further, as ENDO-I shares nucleotide sequence and amino acid sequence with hepatic haptoglobin-which in certain disease states is immunosuppressive and angiogenic-differences in ENDO-I expression and localization in the peritoneal cavity may contribute to the pathogenesis of endometriosis and/or facilitate development of unprecedented diagnostic or therapeutic approaches for management of this enigmatic disease.

Postablative risk of endometrial carcinoma in New Zealand white rabbits given high-dose estrogen.

OBJECTIVE: To follow a population at high risk for endometrial carcinoma after endometrial ablation, to determine if ablation alters the incidence or detection of endometrial pathology. STUDY DESIGN: The animal model included 33 New Zealand white rabbits. Of this cohort, 17 underwent surgical ablation of the endometrium via laparotomy, while 16 served as controls. Vaginal bleeding was assessed with monthly cotton swab examinations as well as daily observation of the subjects. All animals received unopposed estrogen for 18 months prior to necropsy. RESULTS: No animal in either arm of the study demonstrated vaginal bleeding. Two rabbits from the ablation group and three controls showed histologic evidence of atypical endometrial hyperplasia or adenocarcinoma (P > .20). One additional animal from each group had hyperplasia without atypia. CONCLUSION: This animal model suggests that endometrial ablation does not decrease the risk of endometrial carcinoma in patients at high risk of developing endometrial pathology. Detection of hyperplasia or carcinoma in such a population may prove difficult due to the absence of traditional signs of endometrial abnormalities.

Kielland vs. nonrotational forceps for the second stage of labor.

OBJECTIVE: To examine and compare maternal and neonatal morbidity after use of two types of obstetric forceps used in the management of the second stage of labor. STUDY DESIGN: This retrospective investigation was conducted from January 1993 to December 1995 and included 55 infants delivered with Kielland forceps as compared to 213 infants delivered with nonrotational forceps. The maternal and neonatal charts were reviewed for data collection. Maternal complications compared included blood loss, vaginal lacerations, postpartum hemorrhage, and third- and fourth-degree perineal lacerations. Infant data collected compared fetal lacerations, nerve palsies, shoulder dystocias, blood gas values and admissions to the neonatal intensive care unit. Statistical analysis was performed by Fisher's exact, chi 2 and Student's t test. RESULTS: Women in both groups were similar with respect to age, gravidity, parity and estimated gestational age at delivery. Infants were similar in both groups with respect to fetal weight, admissions to the neonatal intensive care unit, nerve compromise, scalp lacerations and facial bruising. The Kielland group had statistically significantly longer labor, 671 +/- 285.8 vs. 614 +/- 226.5 minutes (P < .05) and longer second stage of labor 184 +/- 74.71 vs. 161 +/- 65.79 minutes (P < .05). The Kielland group also had a statistically higher percentage of one-minute Apgar scores < 6, 18.2% vs. 4.7% (P < .05), and meconium present at delivery, 14.5% vs. 5.6% (P < .05). CONCLUSION: Management of the second stage of labor can be accomplished safely with Kielland forceps and rotation of the fetal head. Supervision by an experienced operator will allow residents to be trained with respect to appropriate patient selection and application of these forceps.

Reagentless blood analysis by near-infrared Raman spectroscopy.

BACKGROUND: Raman spectroscopy has advantages over infrared absorption spectroscopy. Combined with a novel multivariate technique, hybrid linear analysis (HLA), low prediction error is expected. METHODS: A near-infrared (NIR) light source excited Raman signals, and a charge coupled device (CCD) camera was used to collect the signal. Samples were collected from 69 individuals for 7 weeks. The standard multivariate calibration technique, partial least squares (PLS) and HLA were both used to analyze the collected spectra. A Clarke error grid was used to evaluate the usefulness of the glucose measurement in serum. RESULTS: The root mean squared error of prediction (RMSEP) for glucose in serum obtained with PLS is 21 mg/dL, and the RMSEP obtained with HLA is 17 mg/dL. In whole blood, the PLS RMSEP for glucose was 79 mg/dL, and HLA predictions had an RMSEP of 63 mg/dL. CONCLUSIONS: The measurement technique was robust over the 7-week period. HLA was shown to generate a lower prediction error than PLS. The predictions by both PLS and HLA were clinically acceptable. The result with whole blood requires further improvement.

Multicomponent blood analysis by near-infrared Raman spectroscopy.

We demonstrate the use of Raman spectroscopy to measure the concentration of many important constituents (analytes) in serum and whole blood samples at physiological concentration in vitro across a multipatient data set. A near-infrared (830-nm) diode laser generates Raman spectra that contain superpositions of Raman signals from different analytes. Calibrations for glucose, cholesterol, urea, and other analytes are developed by use of partial least-squares cross validation. We predict six analytes in serum with significant accuracy in a 66-patient data set, using 60-s spectra. The calibrations are shown to be fairly robust against system drift over the span of seven weeks. In whole blood, a preliminary analysis yields accurate predictions of some of the same analytes and also hematocrit. The results hold promise for potential medical applications.

Evaluating noise induced hearing loss with distortion product otoacoustic emissions.

This study assessed the clinical efficacy of screening for noise induced hearing loss (NIHL) with distortion product otoacoustic emissions (DPOAE). DPOAEs were recorded from 76 military personnel (137 ears) aged between 17 and 41 years in response to equilevel 70 dB SPL primary stimulating tones. The 2f1-f2 DPOAE levels were correlated with audiometric thresholds at frequencies close to f2. Ears with normal audiograms, but with a history of military noise exposure, had DPOAEs that were significantly decreased in amplitude as compared to the ears of normal hearing non-exposed to noise subjects. These ears also had an increased absence of DPOAEs as compared with the ears of the normal hearing non-exposed to noise subjects. Although, in general, the DPOAE amplitudes and spectral frequency ranges reflected the audiometric NIHL configurations, in a number of cases DPOAEs were present for hearing losses up to 75 dB HL. As a consequence, DPOAEs correlated moderately and negatively with the audiometric thresholds. Applying test criteria designed to logically reflect NIHL, DPOAE sensitivity and specificity levels ranged between 0.51-0.90 and 0.63-0.25, respectively. These findings indicate that DPOAEs, recorded and analysed as described, are not sufficiently sensitive to serve as a single test to identify NIHL.

Halitosis: an interdisciplinary approach.

PURPOSE: To summarize the experience in our halitosis clinic, emphasizing an interdisciplinary approach. PATIENTS AND METHODS: Thirty-nine patients with a primary complaint of halitosis were evaluated. Their health was established by a questionnaire, by clinical examination, and by laboratory analysis. Halitosis was evaluated organoleptically by a dentist and an otolaryngologist (odds ratio [OR] = 5.7). The volatile sulfide levels were measured with a portable sulfide monitor (Halimeter; RH-17 series, Interscan, Chatsworth, CA). RESULTS: The patients were found to suffer from otolaryngological disorders (26%), dental problems (23%), oral discomfort (18%), and gastrointestinal pathology (10%), or several of the above. In 31% of the patients, however, no clinical involvement was detected. The salivary flow rates in the patients were similar to those in healthy controls, whereas their oral Candida carrier rate was low (28%). Fifty-seven percent of the patients had objective halitosis by organoleptic evaluation and 61% by Halimeter measurement. CONCLUSION: A high percentage of the patients who came to the clinic with a primary complaint of halitosis did not have a detectable problem.

Detailed analysis of auditory brainstem responses in patients with noise-induced tinnitus.

The role of the auditory brainstem in tinnitus is questionable. This study aimed comprehensively to assess auditory brainstem responses (ABRs) in patients suffering from noise-induced tinnitus (NIT). ABRs were recorded from 13 chronic NIT patients (21 ears) and 11 (21 ears) age and hearing matched control subjects without tinnitus. ABRs were recorded with scalp electrodes placed ipsilateral and contralateral to the stimulated ear, and in three orthonormal differential configurations. The ABRs were analyzed as a function of time, frequency and voltage space. A significantly enhanced ipsilaterally recorded, time domain wave III amplitude was observed for the tinnitus patients. This finding was not confirmed by any of the other ABR measures, which were indistinguishable between subject groups. Although this may be a spurious result, it nonetheless may point to an alteration in the functioning of the putative wave III auditory brainstem generator, which deserves further study.

Beneficial effects of felodipine on myocardial and coronary function during low-flow ischemia and reperfusion.

An acute coronary occlusion causes severe low-flow ischemia in the occluded region. Calcium antagonists have the potential to reduce the rate of ischemic injury by decreasing myocardial oxygen demand, as well as by other mechanisms, especially when given prior to the onset of ischemia. However, their clinical use may be limited by their negative inotropic effects. The purpose of this study was to assess the effects of felodipine as a potentially protective agent against myocardial ischemia and reperfusion injury, independent of any negative inotropic actions, when given after the onset of low-flow ischemia. Isolated isovolumic (balloon-in-LV), blood-perfused rabbit hearts, paced at a constant heart rate, were subjected to 90 minutes of low-flow ischemia at a coronary perfusion pressure of 10 mmHg, which reduced coronary blood flow to 22-24% of baseline. After 15 minutes of low-flow ischemia, hearts received 2 x 10(-6) M felodipine (n = 7) or no drug (controls, n = 8). Felodipine was given until 15 minutes of reperfusion. During low-flow ischemia both groups of hearts had identical coronary blood flow, heart rate, left ventricular (LV) developed pressure, lactate production, and O2 consumption. However, felodipine markedly protected against ischemic diastolic dysfunction. At the end of low-flow ischemia, LV end-diastolic pressure (LVEDP) had increased from 10 +/- 1 to 28 +/- 5 mmHg in the felodipine group, while in the controls LVEDP increased to 48 +/- 8 mmHg (p < 0.05). During 30 minutes of reperfusion, felodipine had a beneficial effect upon coronary blood flow (initial postischemic hyperemia 245 +/- 38% of baseline in the felodipine group vs. 124 +/- 18% in the controls; p < 0.01) Felodipine markedly improved the recovery of contractile function [LV developed pressure recovered from a baseline of 104 +/- 4 to 75 +/- 6 mmHg (72%) in the felodipine group vs. 34 +/- 10 mmHg (32%) in the control group; p < 0.01], as well as diastolic function (LVEDP = 25 +/- 4 mmHg in the felodipine group vs. 61 +/- 10 mmHg in the controls; p < 0.05), and ATP levels (8.5 +/- 1.4 mumoles/g d.w. in the felodipine group vs. 3.9 +/- 1.4 mumoles/g d.w. in the control group, p < 0.05). Felodipine, given after the onset of low-flow ischemia, protects the myocardium during both ischemia and reperfusion by mechanisms other than reducing myocardial oxygen demand.

Noise-induced otoacoustic emission loss with or without hearing loss.

The association between audiometric hearing thresholds and click-evoked otoacoustic emission (CEOAE) spectral properties was examined in 129 adult subjects with and without a noise-induced hearing loss (NIHL). Subjects were grouped according to their "beginning of hearing loss frequency" and their exposure to hazardous noise. Emissions were recorded with an ILO88 Otodynamic Analyzer (Version 2.9) used in the default mode. CEOAE levels decreased as the hearing threshold increased at each of the test frequencies (1,2,3, and 4 kHz). At frequencies where hearing thresholds were worse than 20 dB HL, CEOAEs could not be recorded. Thus as the "beginning of hearing loss frequency" decreased, the frequency range of the emissions became narrower. The hearing threshold for which emissions were not recorded varied significantly between subjects, such that even at frequencies where the hearing threshold was 0 dB HL emissions were not always observed. Noise-exposed, normal-hearing subjects had reduced overall CEOAE power with a narrow frequency range as compared with normal-hearing, nonexposed to noise subjects. For our test conditions, the presence of CEOAEs necessarily suggests hearing thresholds of 20 dB HL or less at the corresponding frequency. A lack of emissions does not necessarily indicate hearing thresholds beyond 20 dB HL.