Natural history of idiopathic erythrocytosis - A retrospective case series review

Idiopathic Erythrocytosis (IE) is a diagnosis given to patients who have an absolute erythrocytosis (red cell mass more than 25% above their mean normal predicted value) but who do not have a known form of primary or secondary erythrocytosis (BCSH guideline, 2005). We report here the results of a follow-up study of 80 patients (44 male and 36 female) diagnosed with IE from the United Kingdom and the Republic of Ireland over a 10 year period. Baseline information was initially collected when investigating for molecular causes of erythrocytosis in this group. The diagnosis of IE was made on the basis of a raised red cell mass >25% above mean normal predicted value, absence of Polycythaemia Vera (PV) based on the criteria of Pearson and Messinezy (1996), and the exclusion of secondary erythrocytosis (oxygen saturation >92% on pulse oximetry, no history of sleep apnoea, no renal or hepatic pathology, and a normal oxygen dissociation curve (if indicated). The average age at diagnosis of erythrocytosis was 34.5 (2–74 years). Erythropoietin levels were available for 77/80 of the patients and were low in 18 (23%) and normal or high in 59 (74%). Ultrasound imaging was carried out in 67 patients (84%) at time of diagnosis and no significant abnormalities found. Fourteen patients had a family history of erythrocytosis. These patients have now been followed up for an average of 9.4 years (range 1–39). Out of 80 patients 56 patients can still be classified as having IE, of whom 52 are living (cause of death in the other 4 - lung cancer, RTA, sepsis, unknown). Thirty-five of these patients are regularly venesected, 3 take hydroxyurea (one also venesected), 11 receive no treatment while treatment is unknown in 2. Twenty take aspirin, 1 warfarin and 31 no thromboprophylaxis. Four of these patients had suffered thromboembolic complications (3 with CVA/TIAs and 1 with recurrent DVT) at or before their original diagnosis. Since diagnosis 8 patients have had 9 thrombotic events of which 7 were arterial (1 CVA, 3 TIAs, 1 MI, 2 PVD) and 2 venous (DVT/PE). Twenty take aspirin, 1 dipyridamole, 1 warfarin and 30 take no thromboprophylaxis. Out of the 24 patients who now have a diagnosis other than IE, 8 have been diagnosed with myelo-proliferative disease. Thirteen patients have a molecular abnormality which is likely to account for their erythrocytosis (11 VHL, 1 PHD-2, 1 EPO-receptor mutations). Three patients have secondary erythrocytosis. Older case studies identified a heterogenous group of patients, some of whom probably had apparent erythrocytosis and some who had either primary polycythaemia or secondary causes later identified (Modan and Modan, Najean et al). More recent reviews have identified a more homogenous group with low rates of transformation to myelofibrosis/acute leukaemia and low rates of thrombosis of around 1% patient-year. Follow up of our initial patient group does indeed reveal a heterogeneous group of patients with 10% now diagnosed with an MPD, although when analysis is confined to those patients who continue to fulfil the criteria for IE, the clinical course has been more stable. There has been no progression to MDS or leukaemia in this group (one patient with PV progressed to AML). The rate of thrombosis is 1.6% patient-years which is lower than the rate seen in PV and is consistent with the rate identified in other series. Molecular defects continue to be identified in this group and future investigation is likely to reveal further abnormalities.

Limbal stem cell deficiency and ocular phenotype in ectrodactyly-ectodermal dysplasia-clefting syndrome caused by p63 mutations

Objective: To describe the ocular phenotype in patients with ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome (MIM#604292) and to determine the pathogenic basis of visual morbidity. Design: Retrospective case series. Participants: Nineteen families (23 patients) affected by EEC syndrome from the United Kingdom, Ireland, and Italy. Methods: General medical examination to fulfill the diagnostic criteria for EEC syndrome and determine the phenotypic severity. Mutational analysis of p63 was performed by polymerase chain reaction-based bidirectional Sanger sequencing. All patients with EEC syndrome underwent a complete ophthalmic examination and ocular surface assessment. Limbal stem cell deficiency (LSCD) was diagnosed clinically on the basis of corneal conjunctivalization and anatomy of the limbal palisades of Vogt. Impression cytology using immunofluorescent antibodies was performed in 1 individual. Histologic and immunohistochemical analyses were performed on a corneal button and corneal pannus from 2 EEC patients. Main Outcome Measures: The EEC syndrome phenotypic severity (EEC score), best-corrected Snellen visual acuity (decimal fraction), slit-lamp biomicroscopy, tear function index, tear breakup time, LSCD, p63 DNA sequence variants, impression cytology, and corneal histopathology. Results: Eleven heterozygous missense mutations in the DNA binding domain of p63 were identified in all patients with EEC syndrome. All patients had ocular involvement and the commonest was an anomaly of the meibomian glands and lacrimal drainage system defects. The major cause of visual morbidity was progressive LSCD, which was detected in 61% (14/23). Limbal stem cell deficiency was related to advancing age and caused a progressive keratopathy, resulting in a dense vascularized corneal pannus, and eventually leading to visual impairment. Histologic analysis and impression cytology confirmed LSCD. Conclusions: Heterozygous p63 mutations cause the EEC syndrome and result in visual impairment owing to progressive LSCD. There was no relationship of limbal stem cell failure with the severity of EEC syndrome, as classified by the EEC score, or the underlying molecular defect in p63. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2012 American Academy of Ophthalmology.

Studies to Reduce Unnecessary Medication Use in Frail Older Adults:A Systematic Review

BACKGROUND: Overuse of unnecessary medications in frail older adults with limited life expectancy remains an understudied challenge. OBJECTIVE: To identify intervention studies that reduced use of unnecessary medications in frail older adults. A secondary goal was to identify and review studies focusing on patients approaching end of life. We examined criteria for identifying unnecessary medications, intervention processes for medication reduction, and intervention effectiveness. METHODS: A systematic review of English articles using MEDLINE, EMBASE, and International Pharmaceutical Abstracts from January 1966 to September 2012. Additional studies were identified by searching bibliographies. Search terms included prescription drugs, drug utilization, hospice or palliative care, and appropriate or inappropriate. A manual review of 971 identified abstracts for the inclusion criteria (study included an intervention to reduce chronic medication use; at least 5 participants; population included patients aged at least 65 years, hospice enrollment, or indication of frailty or risk of functional decline-including assisted living or nursing home residence, inpatient hospitalization) yielded 60 articles for full review by 3 investigators. After exclusion of review articles, interventions targeting acute medications, or studies exclusively in the intensive care unit, 36 articles were retained (including 13 identified by bibliography review). Articles were extracted for study design, study setting, intervention description, criteria for identifying unnecessary medication use, and intervention outcomes. RESULTS: The studies included 15 randomized controlled trials, 4 non-randomized trials, 6 pre-post studies, and 11 case series. Control groups were used in over half of the studies (n = 20). Study populations varied and included residents of nursing homes and assisted living facilities (n = 16), hospitalized patients (n = 14), hospice/palliative care patients (n = 3), home care patients (n = 2), and frail or disabled community-dwelling patients (n = 1). The majority of studies (n = 21) used implicit criteria to identify unnecessary medications (including drugs without indication, unnecessary duplication, and lack of effectiveness); only one study incorporated patient preference into prescribing criteria. Most (25) interventions were led by or involved pharmacists, 4 used academic detailing, 2 used audit and feedback reports targeting prescribers, and 5 involved physician-led medication reviews. Overall intervention effect sizes could not be determined due to heterogeneity of study designs, samples, and measures. CONCLUSIONS: Very little rigorous research has been conducted on reducing unnecessary medications in frail older adults or patients approaching end of life.

Fundus autofluorescence in the diagnosis of cystoid macular oedema

Aim: To determine the sensitivity and specificity of the non-invasive imaging technique, fundus autofluorescence (AF), in the diagnosis of cystoid macular oedema (CMO), using fluorescein angiography as the reference standard. Design: Retrospective, consecutive, observational case series. Methods: Ninety-six consecutive patients with CMO suspected clinically were selected from the AF database of the Retina Unit, Ophthalmology Department, Grampian University Hospitals-NHS Trust, between August 2004 and June 2006. Only patients in whom CMO was secondary to (1) cataract extraction, (2) inherited retinopathies, (3) inflammatory eye disease or (4) idiopathic cases were included in this study. Only patients in whom AF images had been performed within 2 weeks of FFA and, when obtained following FFA, there was a minimum gap of 4 days ("washing out" period), were considered eligible for this study. A total of 34 eyes from 34 patients were eligible and were included in this study. FFA was used as the reference test to confirm the presence of CMO, and, based on fluorescein angiography (FFA), CMO was graded as either mild or florid. AF images were examined in a masked fashion for the presence or absence of CMO. The sensitivity and specificity of AF in detecting CMO were then calculated. Results: CMO was seen on AF imaging as round or oval areas at the fovea with an AF signal similar to that of background levels. At this site (fovea), the AF signal is usually reduced compared with background, due to the blockage caused by luteal pigment. The diagnosis of CMO based on AF imaging had 81% sensitivity and 69% specificity when compared with the reference standard FFA. Based on the FFA, there were 12 cases of florid CMO and eight of mild CMO. Of the former, CMO was detected with AF imaging in 100% (12/12 eyes), and of the latter, in 50% (4/8 eyes). Conclusions: AF imaging can be used as a rapid, non-invasive technique in the diagnosis of CMO.

Progression of retinal pigment epithelial atrophy in stargardt disease

• PURPOSE: To evaluate retinal pigment epithelial (RPE) atrophy in patients with Stargardt disease using autofluorescence imaging (AF). • DESIGN: Retrospective observational case series. • METHODS: Demographics, best-corrected visual acuity (BCVA), AF images, and electrophysiology responses (group 1, macular dysfunction; group 2, macula + cone dysfunction; group 3, macula + cone-rod dysfunction) were evaluated at presentation and follow-up in a group of 12 patients (24 eyes) with Stargardt disease. The existence, development, and rate of enlargement of areas of RPE atrophy over time were evaluated using AF imaging. A linear regression model was used to investigate the effects of AF and electrophysiology on rate of atrophy enlargement and BCVA, adjusting for age of onset and duration of disease. • RESULTS: Eight male and 4 female patients (median age 42 years; range 24-69 years) were followed for a median of 41.5 months (range 13-66 months). All 12 patients had reduced AF compatible with RPE atrophy at presentation and in all patients the atrophy enlarged during follow-up. The mean rate of atrophy enlargement for all patients was 1.58 mm /y (SD 1.25 mm /y; range 0.13-5.27 mm /y). Only the pattern of functional loss present as detected by electrophysiology was statistically significantly associated with the rate of atrophy enlargement when correcting for other variables (P <.001), with patients in group 3 (macula + cone-rod dysfunction) having the fastest rate of atrophy enlargement (1.97 mm /y, SD 0.70 mm /y) (group 1 [macula] 1.09 mm /y, SD 0.53 mm /y; group 2 [macula + cone] 1.89 mm /y, SD 2.27 mm /y). • CONCLUSION: Variable rates of atrophy enlargement were observed in patients with Stargardt disease. The pattern of functional loss detected on electrophysiology was strongly associated with the rate of atrophy enlargement over time, thus serving as the best prognostic indicator for patients with this inherited retinal disease. © 2012 Elsevier Inc. All rights reserved.

New surgical approach in the management of pseudophakic malignant glaucoma

Purpose: To describe a new surgical approach in the management of pseudophakic malignant glaucoma. Design: Noncomparative case series. Participants: Five consecutive patients with pseudophakic malignant glaucoma. Methods: All patients underwent zonulo-hyaloido-vitrectomy. The procedure involves the performance of zonulectomy, hyaloidectomy, and anterior vitrectomy (zonulo-hyaloido-vitrectomy) through a peripheral iridectomy or iridotomy via the anterior chamber. Main Outcome Measures: Medications, visual acuity, intraocular pressure, and anterior and posterior segment findings were recorded before and after surgery. Results: Resolution of the malignant glaucoma was achieved in all cases. No recurrences were observed after a median follow-up of 5.5 months (range, 1-9 months). In one patient with extensive anterior synechiae, bleb failure occurred after the resolution of the malignant glaucoma. This patient was treated successfully with a guarded filtration procedure supplemented with 5-fluorouracil. No other complications were observed. Conclusions: Zonulo-hyaloido-vitrectomy via the anterior segment appears to be an alternative option in the treatment of patients with pseudophakic malignant glaucoma. © 2001 by the American Academy of Ophthalmology.

Primary cysts of the iris pigment epithelium. Clinical features and natural course in 234 patients

Objective: To describe the clinical characteristics, natural course, and complications of a large group of patients with primary iris pigment epithelium (IPE) cysts. Design: Observational case series. Participants: Two hundred thirty-four patients with primary IPE cysts participated. Results: Primary IPE cysts were classified as central in 6 patients (3%), midzonal in 50 patients (21%), peripheral in 170 patients (73%), and dislodged in 8 patients (3%). Central (pupillary) IPE cysts were found only in males, peripheral IPE cysts were found most often in females (69%), and no gender predilection was detected for midzonal and dislodged IPE cysts. Central and peripheral IPE cysts occurred in young patients (mean age, 20 and 33 years, respectively), whereas midzonal and dislodged IPE cysts were seen in slightly older patients (mean age, 52 and 45 years, respectively). Central IPE cysts were visible when the pupil was not dilated and appeared most often as a round or collapsed brown lesion arising from the pupillary margin, most commonly superonasally. Midzonal IPE cysts were brown and fusiform, best visualized after pupillary dilation. Peripheral IPE cysts produced a characteristic bulging in the iris stroma near the iris root, but they were directly visible in only 78% of cases. After wide dilation and patient and slit-lamp positioning, they appeared as a round clear lesion behind the iris, most often in the inferotemporal quadrant. Finally, dislodged IPE cysts appeared as a brown oval lesion, free floating in the anterior chamber (12%) or in the vitreous (12%), or fixed in the anterior chamber angle (75%). One hundred twenty-four patients (53%) were followed for a mean of 35 months (range, 3 months-19 years). In these patients, complications associated with IPE cysts included lens subluxation in one case (1%), iritis in one case (1%), focal cataract in two cases (2%), glaucoma in two cases (2%), and corneal touch in five cases (4%). Conclusion: Primary IPE cysts have characteristic clinical features that serve to differentiate them from intraocular malignancies. Most cysts have a benign clinical course, and treatment is rarely necessary.

Use of perfluorohexyloctane as a long-term internal tamponade agent in complicated retinal detachment surgery

PURPOSE: To report the use of perfluorohexyloctane, a liquid semifluorinated alkane that is heavier than water, as an internal tamponade agent in surgery for complicated retinal detachments. DESIGN: A consecutive interventional case series from three study centers. METHODS: In 23 consecutive eyes (23 patients, 19 men and four women, mean ± standard deviation (SD) age of 58.5 years ± 16.1) perfluorohexyloctane was used for long-term internal tamponade. Included were eyes with complicated retinal detachment involving the lower two quadrants of the fundus. Excluded were patients with diseases in the fellow eye or severe systemic disease. A pars plana vitrectomy was performed, including membrane peeling and retinotomy where necessary. RESULTS: The mean duration for perfluorohexyloctane being left in situ was 76 days (SD 37.64) (range, 35-202 days). Four weeks following the removal of perfluorohexyloctane 19 of the 23 patients had total reattachment of the retina; three eyes had a recurrence of retinal detachment. One patient was lost to follow-up. The mean follow-up after perfluorohexyloctane removal was 97 days (range, 48 to 169 days). Cataract formation or progression was noted in nine of the 10 eyes. There were two cases with high intraocular pressures. Dispersion into small droplets was observed as early as 3 days postoperatively in three of the 23 patients. At least 12 of the 23 patients had an obvious dispersion by the time of perfluorohexyloctane removal. There was no sign of optic atrophy, retinal necrosis, or retinal vascular occlusion. CONCLUSION: Perfluorohexyloctane was tolerated as a long-term internal tamponade agent without obvious signs of damage to the retina or optic disk. Of all the complications noted, the most common was that of dispersion of the perfluorohexyloctane bubble into droplets. © 2002 by Elsevier Science Inc. All rights reserved.

Functional outcomes of decompressive hemicraniectomy following malignant middle cerebral artery infarctions: a systematic review

Decompressive hemicraniectomy has been used increasingly in recent years to treat malignant middle cerebral artery territory infarction. This review examines functional outcome data, with the novel analysis of outcomes according to temporal periods post-surgery. Case series data were pooled to determine significant correlates of outcome. Severe disability was frequently the outcome among survivors within one month post-surgery. Time and rehabilitation were later reflected, with fewer deaths and the emergence of mild to moderate disability increasing in prevalence. Mortality and severe disability were consistently more probable with increasing age. Presurgical clinical status in the form of additional cerebral artery involvement and midline shift also correlated with mortality within the 30-day period post-stroke.

Long-term neuropsychological and psychosocial outcomes of decompressive hemicraniectomy following malignant middle cerebral artery infarctions

Purpose: This study examines long-term neuropsychological and psychosocial outcomes of survivors of malignant middle cerebral artery infarction treated via decompressive hemicraniectomy. Method: A case series design facilitated a detailed analysis of the outcomes among five participants. Neuropsychological domains assessed included premorbid and current IQ, sustained, selective and divided attention, visual and auditory memory, executive functioning and visuo-spatial ability. Psychosocial domains assessed included self-rated depression, anxiety and quality of life. Participants and their main carer were asked about their retrospective view of surgery. Results: All participants showed neuropsychological impairments in multiple cognitive domains, with preserved ability in others. Effects of laterality of brain function were evident in some domains. Clinically significant depression was evident in two participants. Overall quality of life was within average limits in three of four assessed participants. Four participants retrospectively considered surgery as having been a favourable course of action. Conclusion: While neuropsychological impairments are highly likely post-surgery, preserved abilities and social support may serve a protective function against depression and an unacceptably poor quality of life. Results do not support the suggestion that decompressive hemicraniectomy following malignant middle cerebral artery infarction necessarily leads to unacceptable neuropsychological or psychosocial outcomes.

Sensitivity and specificity of frequency-doubling technology, tendency-oriented perimetry, and Humphrey Swedish interactive threshold algorithm-fast perimetry in a glaucoma practice

PURPOSE: To evaluate the sensitivity and specificity of the screening mode of the Humphrey-Welch Allyn frequency-doubling technology (FDT), Octopus tendency-oriented perimetry (TOP), and the Humphrey Swedish Interactive Threshold Algorithm (SITA)-fast (HSF) in patients with glaucoma. DESIGN: A comparative consecutive case series. METHODS: This was a prospective study which took place in the glaucoma unit of an academic department of ophthalmology. One eye of 70 consecutive glaucoma patients and 28 age-matched normal subjects was studied. Eyes were examined with the program C-20 of FDT, G1-TOP, and 24-2 HSF in one visit and in random order. The gold standard for glaucoma was presence of a typical glaucomatous optic disk appearance on stereoscopic examination, which was judged by a glaucoma expert. The sensitivity and specificity, positive and negative predictive value, and receiver operating characteristic (ROC) curves of two algorithms for the FDT screening test, two algorithms for TOP, and three algorithms for HSF, as defined before the start of this study, were evaluated. The time required for each test was also analyzed. RESULTS: Values for area under the ROC curve ranged from 82.5%-93.9%. The largest area (93.9%) under the ROC curve was obtained with the FDT criteria, defining abnormality as presence of at least one abnormal location. Mean test time was 1.08 ± 0.28 minutes, 2.31 ± 0.28 minutes, and 4.14 ± 0.57 minutes for the FDT, TOP, and HSF, respectively. The difference in testing time was statistically significant (P <.0001). CONCLUSIONS: The C-20 FDT, G1-TOP, and 24-2 HSF appear to be useful tools to diagnose glaucoma. The test C-20 FDT and G1-TOP take approximately 1/4 and 1/2 of the time taken by 24 to 2 HSF. © 2002 by Elsevier Science Inc. All rights reserved.

A systematic literature review of surgical interventions for limbal stem cell deficiency in humans

PURPOSE: To evaluate the relative benefits and to identify any adverse effects of surgical interventions for limbal stem cell deficiency (LSCD).

DESIGN: Systematic literature review.

METHODS: We searched the following electronic databases from January 1, 1989 through September 30, 2006: MEDLINE, EMBASE, Science citation index, BIOSIS, and the Cochrane Library. In addition, reference lists were scanned to identify any additional reports. The quality of published reports was assessed using standard methods. The main outcome measure was improvement in vision of at least two Snellen lines of best-corrected visual acuity (BCVA). Data on adverse outcomes also were collected.

RESULTS: Twenty-six studies met the inclusion criteria. There were no randomized controlled studies. All 26 studies were either prospective or retrospective case series. For bilateral severe LSCD, keratolimbal allograft was the most common intervention with systemic immunosuppression. Other interventions included eccentric penetrating keratolimbal allografts and cultivated autologous oral mucosal epithelial grafts. An improvement in BCVA of two lines or more was reported in 31% to 67% of eyes. For unilateral severe LSCD, the most common surgical intervention was contralateral conjunctival limbal autograft, with 35% to 88% of eyes gaining an improvement in BCVA of two lines or more. The only study evaluating partial LSCD showed an improvement in BCVA of two lines or more in 39% of eyes.

CONCLUSIONS: Studies to date have not provided strong evidence to guide clinical practice on which surgery is most beneficial to treat various types of LSCD. Standardized data collection in a multicenter LSCD register is suggested.

Reversal of optic disc cupping after glaucoma surgery analyzed with a scanning laser tomograph

Objective: To detect and quantitate changes in optic nerve morphology after glaucoma surgery using the Heidelberg Retina Tomograph (HRT, Heidelberg Instruments, Heidelberg, Germany). Design: Nonconsecutive observational case series. Participants and Intervention: The authors prospectively enrolled 21 adult patients undergoing incisional glaucoma surgery for progressive glaucoma damage. Quantitative analysis of the optic nerve head by scanning laser tomography and automated perimetry were performed before and after glaucoma surgery. Main Outcome Measures: Changes in optic nerve parameters were subjected to linear regression analysis with respect to percent of postoperative reduction of intraocular pressure (IOP), as well as with respect to age, refraction, preoperative cup:disc ratio, and change in visual field parameters. Results: Seventeen patients had pre- and postoperative images suitable for analysis. Mean IOP at the time of image acquisition before surgery was 30.5 ± 12 mmHg, and after surgery 11.8 ± 5.2 mmHg (mean follow-up, 26 ± 7 weeks). Eleven of 13 (85%) patients having IOP reduction of greater than 40% showed improvement in optic disc parameters. All four patients with less than 25% reduction in IOP showed worsening of most parameters. Changes in optic disc parameters were highly correlated with percent IOP reduction and with age. The parameters in which change most strongly correlated with percent change of IOP were cup area, rim area, cup:disc ratio, and mean cup depth (each, P <0.005). The age of the patient correlated highly with change in maximum cup depth (P <0.005). Refraction and clinically determined cup:disc ratio correlated poorly with changes in measured optic disc parameters. Clinical improvement in visual fields was correlated with the degree of improvement of cup:disc ratio (P = 0.025). Conclusion: Most patients showing a 40% lowering of IOP after glaucoma surgery show improved optic nerve morphology as measured by the HRT. The amount of improvement correlated highly with the percent reduction of IOP.

Worked to Death? A census-based longitudinal study of the relationship between the numbers of hours spent working and mortality risk

Background There has been an increasing interest in the health effects of long
working hours, but little empirical evidence to substantiate early
10 case series suggesting an increased mortality risk. The aim of the
current study is to quantify the mortality risk associated with long
working hours and to see if this varies by employment relations and
conditions of occupation.
Methods A census-based longitudinal study of 414 949 people aged 20-59/64
15 years, working at least 35 h/week, subdivided into four occupational
classes (managerial/professional, intermediate, own account workers,
workers in routine occupations) with linkage to deaths records
over the following 8.7 years. Cox proportional hazards models were
used to examine all-cause and cause-specific mortality risk.
20 Results Overall 9.4% of the cohort worked 55 or more h/week, but this
proportion was greater in the senior management and professional
occupations and in those who were self-employed. Analysis of 4447
male and 1143 female deaths showed that hours worked were
associated with an increased risk of all-cause mortality only for
25 men working for more than 55 or more h/week in routine/semiroutine
occupations [adjusted hazard ratios (adjHR) 1.31: 95%
confidence intervals (CIs) 1.11, 1.55)] compared with their peers
working 35–40 h/week. Their equivalent risk of death from cardiovascular
disease was (adjHR 1.49: 95% CIs 1.10, 2.00).
30 Conclusions These findings substantiate and add to the earlier studies indicating
the deleterious impact of long working hours but also suggest that
the effects are moderated by employment relations or conditions of
occupation. The policy implications of these findings are discussed.