Mutations in the bone morphogenetic protein 15 gene causing defective protein secretion in Cholistani infertile sheep / Mutações no gene da proteína morfogenética óssea 15 causadoras de defeitos na secreção proteica em ovelhas inférteis Cholistani

Naturally occurring mutations in morphogenetic protein 15 (BMP15) are associated with decreased ovulation rate (OR), litter size (LS), and sterility. It is of a great interest to elucidate BMP15 gene in Cholistani sheep breed to uplift socio-economic status and the knowledge of Cholistani sheep breeding in Southern Punjab, Pakistan. In our study, a total of 50 infertile Cholistani sheep aged between 2-6 years and having no blood relation were screened for BMP15 mutations. For this purpose, a high-quality DNA was extracted from the blood of sheep followed by primer designing, Polymerase Chain Reaction (PCR) amplification, DNA sequencing, and in silico analyses. Out of total 50 samples, 9 samples including case 1 (T3), case 2 (T8), case 3 (T17), case 4 (T22), case 5 (T25), case 6 (T33), case 7 (T40), case 8 (T44), and case 9 (T47) were found positive for a variety of already reported and novel BMP15 mutations. Further in silico analyses of the observed mutations have shown the functional impact of these mutations on different characteristics (molecular weight, theoretical PI, estimated half-life, instability index, sub-cellular localization, and 3D confirmation) of the encoded proteins, possibly altering the normal functionality. In a nutshell, findings of this study have confirmed the possible essential role of the BMP15 mutations in the infertility of the Cholistani sheep.

Mutações de ocorrência natural na proteína morfogenética 15 (BMP15) estão associadas à diminuição da taxa de ovulação (TO), tamanho da ninhada (TN) e esterilidade. Estudar a BMP15 na raça Cholistani para elevar o status socioeconômico e o conhecimento da criação de ovinos Cholistani no sul de Punjab, Paquistão. Em nosso estudo, 50 ovelhas Cholistani inférteis sem parentesco sanguíneo foram rastreadas para mutações BMP15. Para tanto, um DNA de alta qualidade foi extraído do sangue dessas ovelhas, seguido de concepção do primer, amplificação da reação em cadeia da polimerase (PCR), sequenciamento de DNA e análises in silico. Do total de 50 amostras, 9, incluindo caso 1 (T3), caso 2 (T8), caso 3 (T17), caso 4 (T22), caso 5 (T25), caso 6 (T33), caso 7 (T40), caso 8 (T44) e caso 9 (T47), foram consideradas positivas para uma variedade de mutações BMP15 novas e já relatadas. Mais análises in silico das mutações observadas mostraram o impacto funcional dessas mutações em diferentes características (peso molecular, PI teórico, meia-vida estimada, índice de instabilidade, localização subcelular e confirmação 3D) das proteínas codificadas, possivelmente alterando a funcionalidade normal. Nossos achados confirmaram o possível papel essencial das mutações BMP15 na infertilidade de ovelhas Cholistani.

Mutations in the bone morphogenetic protein 15 gene causing defective protein secretion in Cholistani infertile sheep

Abstract Naturally occurring mutations in morphogenetic protein 15 (BMP15) are associated with decreased ovulation rate (OR), litter size (LS), and sterility. It is of a great interest to elucidate BMP15 gene in Cholistani sheep breed to uplift socio-economic status and the knowledge of Cholistani sheep breeding in Southern Punjab, Pakistan. In our study, a total of 50 infertile Cholistani sheep aged between 2-6 years and having no blood relation were screened for BMP15 mutations. For this purpose, a high-quality DNA was extracted from the blood of sheep followed by primer designing, Polymerase Chain Reaction (PCR) amplification, DNA sequencing, and in silico analyses. Out of total 50 samples, 9 samples including case 1 (T3), case 2 (T8), case 3 (T17), case 4 (T22), case 5 (T25), case 6 (T33), case 7 (T40), case 8 (T44), and case 9 (T47) were found positive for a variety of already reported and novel BMP15 mutations. Further in silico analyses of the observed mutations have shown the functional impact of these mutations on different characteristics (molecular weight, theoretical PI, estimated half-life, instability index, sub-cellular localization, and 3D confirmation) of the encoded proteins, possibly altering the normal functionality. In a nutshell, findings of this study have confirmed the possible essential role of the BMP15 mutations in the infertility of the Cholistani sheep.

Resumo Mutações de ocorrência natural na proteína morfogenética 15 (BMP15) estão associadas à diminuição da taxa de ovulação (TO), tamanho da ninhada (TN) e esterilidade. Estudar a BMP15 na raça Cholistani para elevar o status socioeconômico e o conhecimento da criação de ovinos Cholistani no sul de Punjab, Paquistão. Em nosso estudo, 50 ovelhas Cholistani inférteis sem parentesco sanguíneo foram rastreadas para mutações BMP15. Para tanto, um DNA de alta qualidade foi extraído do sangue dessas ovelhas, seguido de concepção do primer, amplificação da reação em cadeia da polimerase (PCR), sequenciamento de DNA e análises in silico. Do total de 50 amostras, 9, incluindo caso 1 (T3), caso 2 (T8), caso 3 (T17), caso 4 (T22), caso 5 (T25), caso 6 (T33), caso 7 (T40), caso 8 (T44) e caso 9 (T47), foram consideradas positivas para uma variedade de mutações BMP15 novas e já relatadas. Mais análises in silico das mutações observadas mostraram o impacto funcional dessas mutações em diferentes características (peso molecular, PI teórico, meia-vida estimada, índice de instabilidade, localização subcelular e confirmação 3D) das proteínas codificadas, possivelmente alterando a funcionalidade normal. Nossos achados confirmaram o possível papel essencial das mutações BMP15 na infertilidade de ovelhas Cholistani.

Management of displaced transverse fractures of the patella using tension band wiring with or without circumferential cerclage wiring: A comparative study

Background: Transverse fractures of body of the patella are by far the most common fractures of this bone. Surgical fixation is the recommended treatment in displaced fractures with extensor lag. Although, tension band wiring (TBW) technique is the gold standard for these fractures, few surgeons recommend augmentation with circumferential cerclage wiring to improve the strength of the fixation. We compared the results of the internal fixation of displaced transverse fractures of the patella using TBW and circumferential cerclage wiring with those treated with TBW alone. Methods: We treated 54 displaced transverse fractures of the patella at our institution. We segregated the patients into two groups: Group 1 (n=23) included fractures treated with tension band wiring (TBW) along with augmented circumferential cerclage wiring while as Group 2 (n=31) included fractures treated by TBW alone. Outcome was studied, graded and compared on the basis of knee pain, knee stiffness, quadriceps wasting, loss of flexion and loss of extension. Results: 73.90% patients among group 1 and 70.96% among group 2 showed excellent to good results (P value < 0.1). Fixation failure and need for revision surgery among group 1 and group 2 was found to be 8.69% and 9.67%, respectively (P value < 0.6). Infections and non union occurred among 4.34% patients in group 1 whereas in group 2 it was 6.45% of the patients who encountered the same (P value < 0.6). Conclusions: The use of circumferential cerclage wiring along with tension band wiring for displaced transverse fractures of patella seems to have no added advantage over fixation with tension band wiring alone. Keywords: Patella fracture, Tension band wiring, cerclage wiring

public purchase of aphrodisiac products without prescriptions in the Alahsa region of KSA

Objectives: To investigate requests for common prescription-only aphrodisiacs across community pharmacies in the Alahsa region of KSA

Methods: A cross-sectional study was conducted among conveniently selected pharmacies in the eastern region of Alahsa, KSA. Self-administered questionnaires were directly distributed to 73 consenting community pharmacies. Completed questionnaires were coded, reviewed for accuracy and entered into a database in Statistical Package for the Social Sciences [Version 19.0; IBM Corporation, Somers, NY]. The data were analysed using descriptive analysis

Results: The survey response rate was 72.60%. With respect to the availability of aphrodisiacs and sexual supplements, most of the pharmacists disclosed that they had stocks of Viagra and Cialis. The most common men's health complication reported by pharmacists was erectile dysfunction [n ¼ 12, 22.6%], followed by premature ejaculation [n ¼ 4, 7.5%] and low sexual desire [n ¼ 1, 1.9%]. Less than half of pharmacists [n ¼ 9, 16.9%] cited Viagra and Cialis as preferred drugs for treating premature ejaculation. Approximately 32 [60.3%] proposed delayed sprays as the first line of action, while 13 [24.5%] considered antidepressants as their first-choice drug

Conclusion: The non-prescription dispensing of prescription-only medicines, including sexual enhancement products, is common in KSA. The majority of pharmacists continue to violate pharmaceutical laws

Testicular and paratesticular non- neoplastic lesions in university of maiduguri teaching hospital: a 10-year retrospective review

Objectives: The present study is undertaken to describe the spectrum of histopathological features and age distribution of non-neoplastic testicular and paratesticular lesions in the University of Maiduguri Teaching Hospital (UMTH). Materials and methods: A retrospective descriptive study of 70 testicular and paratesticular nonneoplastic lesions was conducted over a period of 10 years; between January-2005 and December2014 in the Department of Histopathology, UMTH. Histopathological examination was done after routine processing and staining with Haematoxylin and Eosin. Special stain (Ziehl-Neelsen stain) was done to confirm the presence of acid fast bacilli in cases of tuberculous epididymoorchitis. Results: There were of which (24.3%) followed by testicular torsion and infarction (14.3%). The youngest patient was 2 years old and the oldest was 80 years of age. The highest incidence occurred in the age range of 30 ­ 59 years with a total of 25 cases representing 35.7%. The lowest incidence was observed in the elderly (= 60 years) with a total of 21 cases (30%). Conclusion: This study shows that inflammatory disorders are the predominant causes of the testicular and paratesticular non-neoplastic lesions capable of interfering with fertility and mimicking malignancy. There is also the need to emphasise the necessity of proper evaluation and treatment of acute orchitis and microabscess to avoid unnecessary orchidectomy.70 cases of non-neoplastic testicular and paratesticular lesions the majority were inflammatory disorders accounting for 53 cases (75.7%). They included acute orchitis (4.3%), tuberculosis (12.9%), schistosomiasis (8.6%), hydrocoele (24.3%), chronic orchitis (10.0%), epididymal cyst (11.4%) and tumoral calcinosis (4.3%). Other categories of the lesions included congenital abnormalities (10.0%) and traumatic disorder (14.3%). Long-standing hydrocoele was the commonest lesion

Frequency and pattern of cytogenetic alterations in primary amenorrhea cases of Kashmir, North India

Background: Primary amenorrhea [PA] is proposed to have multiple etiological factors that include genetic factors, intrauterine malformations, endocrine dysfunction and environmental factors, as revealed by previous studies pertaining to amenorrhea. However, among the various proposed etiologies, genetic factors appear to be highly associated with PA as approximately 40% of PA cases have been found to have genetic causes

Aim of the study: The present study was proposed to establish the frequency and pattern of chromosomal abnormalities in PA cases of Kashmir

Subjects and methods: A total of 108 females within the age group of 14-33 years and having a history of amenorrhea were included in the study. Peripheral blood lymphocyte cultures were set for each subject according to standard protocol and chromosomal analysis was carried out on well spread metaphases by the help of Cytovision software Version 3.9

Results: The results of the present study reveal that the incidence of chromosomal abnormalities in PA cases of this region is almost similar with those of many reports around the world. However, we report two unique chromosomal alterations viz., 46, XX, dup2q[13] and 46,XX, t[2,5][p11.2;q34] that have not been found elsewhere in the literature

Conclusion: The results of the present study indicate that chromosomal analysis of females with PA, after the exclusion of nongenetic causes, should be essentially considered for the precise diagnosis and the development of more successful treatment. The study being the first of its kind in this part of the world forms the basis for further studies of the PA cases of this region. The precise molecular characterization of the unique breakpoint regions reported in our study can possibly help in the identification of new genes involved in primary amenorrhea

Cytogenetic diagnosis of Roberts SC phocomelia syndrome: first report from Kashmir

There are several syndromes in which specific mitotic chromosomal abnormalities can be seen, like premature centromere separation, premature [sister] chromatid separation, and somatic aneuploidies. Identifications of such specific cytogenetic findings can be the key factor that leads towards the diagnosis of syndromes like Roberts SC phocomelia. The case presented here as Roberts SC phocomelia syndrome was identified as a child with multiple congenital anomalies and dysmorphic features. Conventional cytogenetic analysis of the case revealed premature sister chromatid separation. The premature centromeric separation was also confirmed by C banding analysis of the child. It is the first and the only case of Roberts SC phocomelia diagnosed from this part of the world. The present case report emphasizes the importance of conventional cytogenetics in the diagnosis of such syndromes

Role of effective communication in management of medical emergencies

Effective and rapid communication in management of day to day medical emergencies can decide between life and death of a particular patient, and life to death of a large number of casualties in case of a major disaster. A systematic approach to develop interpersonal and inter departmental communication needs to be stressed. The newer modes of communication must be incorporated in this system to facilitate speedy approach to the target healthcare facility

Dermatitis Herpetiformis (DH) in Association with H. pylori Infection: Description of a Case Report.

Dermatitis herpetiformis (DH) is an autoimmune blistering disorder associated with a gluten-sensitive enteropathy (GSE), and is generally accepted as a cutaneous manifestation of celiac disease and is characterized by grouped excoriations; erythematous, urticarial plaques; and papules with vesicles. We reported an interesting case of adult DH occurred in a 30 year old Sudanese young adult with chronic inflammatory bowel disease, presented with typical string of pearls in the face, trunk and extremities for 2 months duration. The case is diagnosed and confirmed as DH where histopathologically shows a sub-epidermal bulla with microabscess formation, sigmoidoscopy and H. pylori ELISA test were positive IgA. Our case had an adult onset of presentation. Clinical features and histopathology are typical. It is associated of H. Pylori, although poorly responding to triple therapy (Doxycyclin 100 mg bid for 8 days, Cefixime 400 mg for 5 days and Rabeprazole as proton pump inhibitor (PPI) 20 mg for 28 days), but focusing as possible antigen was of paramount concern as possible causative antigen; as in this case all serological specific tests for Coeliac disease were negative. The case was considered to be the second case of DH with CIBD due to H. Pylori been reported in Sudan.

Coverage and predictors of vaccination among children of 1-4 years of age in a rural sub-district of Sindh

To estimate the proportion of children 1-4 years of age vaccinated in the first year of their life and determine socio-demographic factors associated with vaccination in the rural sub-district Khairpur, Sindh, Pakistan. Cross-sectional study. The study was conducted in 9 Union Councils of sub-district Gambat, district Khairpur, Sindh, from August to October 2008. A questionnaire based representative multi-stage cluster survey was conducted. A total of 549 children aged 1-4 years were assessed for coverage and predictors of vaccination. Univariate and multivariate analysis was done using logistic regression to determine the unadjusted and adjusted relationship between socio-demographic predictor and outcome [vaccination status]. The coverage for complete vaccination was 71.9% [95%CI=68.1%-75.7%]. Educational level of mother [p=0.042], father [p=0.001] and child birth at hospital [p=0.006] were significantly associated with the vaccination status. Mother's educational level of intermediate and above was the strongest predictor [OR=12.19, 95%CI=1.57-94.3] for vaccination. Education of parents, particularly mother's education was important determinant of vaccination status of the children. In addition, distance from taluka health facility and misconception of parents were among the main reasons of not getting the children vaccinated. There is a need to educate the parents especially mothers about the importance of vaccination and organize EPI services at Basic Health Unit level to improve the vaccination coverage in rural areas of Pakistan

Non-fatal limb injuries in motorbike accidents

To determine frequency and pattern of non-fatal limb injuries in motorbike accidents victims. Cross-sectional observational study. Study was conducted at Jinnah Postgraduate Medical Centre [JPMC], Karachi, from October 2006 to March 2007. Trained data collectors prospectively collected data from the emergency department of JPMC, Karachi using structured pre-tested questionnaires. All motorbike accident victims presented to Emergency department with single or multiple bone injury in body extremities were included. Head injury patients who had first presented to neuro-surgery department were excluded. Motorbike accident victims with soft tissue injuries were also excluded from this study. Chi-square test was applied to find out statistical significance at 95% confidence level. P-value <0.05 was considered as significant. A total of 137 [39%] patients presented with tibial injury among the study sample of 348 patients, which was significantly higher than the bone injuries of the body part [p<0.001]. Out of those, in 26% of patients, fibula was also involved along with tibia fracture. Other bone injuries included femur [16%], radius [9.2%], humerus [8.3%] and others. Radius was the commonest injured bone and in highest proportion among upper limb injuries [p<0.001]. Overall, 66% of the injuries in motorbike involved lower limb fractures. The highest proportion of motorbike accidents were observed on Saturdays [31%]. Majority of the accident victims were in the age group between 16 and 30 years [41% accident cases], 27% in age group 30 to 45 years, 15% in 45 to 60 years and 5% in >60 years. Those with less than 15 years accounted for 12% of cases. Tibial bone is at the greatest risk in motorbike accidents probably due to its superficiality and exposed position while riding motorbike. Protective measures need to be taken for the prevention of disability associated with lower limb involvement in motorbike accidents

Immune reconstitution inflammatory syndrome in a patient with cryptococcal lymphadenitis as the first presentation of acquired immunodeficiency syndrome.

Immune reconstitution inflammatory syndrome is commonly seen in acquired immunodeficiency syndrome (AIDS) patients having concomitant opportunistic infection, following initiation of highly active anti-retroviral therapy (HAART). We describe IRIS in a young man with unknown human immunodeficiency virus (HIV) status who presented with cryptococcal lymphadenitis as the first manifestation of AIDS. At presentation the patient had features overlapping with tuberculosis (TB) lymphadenitis which was ruled out by fine needle aspiration cytology. The patient responded to antifungal treatment but following the start of HAART, symptoms recurred which were managed conservatively. Though TB is common in India, a thorough workup including histopathology of lymph node should be done before the patient is started on anti-tuberculosis treatment. HIV infected patients having opportunistic co-infection should be closely monitored following initiation of HAART.

Acute myocardial infarction: evidence for a sex-age interaction

Women with acute myocardial infarction have higher in-hospital mortality than men mainly due to greater age on presentation. To evaluate the age specific sex difference in in-hospital mortality of acute myocardial infarction. Descriptive study. Coronary Care Unit and cardiology ward of Nishtar Hospital Multan from 15th of September 2002 till 30th of April 2003. Four hundred and fifty patients of acute myocardial infarction who fulfilled our inclusion criteria were studied while they were admitted to the hospital. Patients were divided into four groups according to age and sex i.e. Group I [male <45 years], Group II [male >= 45 years], Group III [female <45 years] and Group IV [female >45 years]. In-hospital mortality was compared between different age groups by Chi-square test. The total in-hospital mortality was 76[16.9%]. In Group III none of the patients expired. In Group I in-hospital mortality was 6[7.1%] patients followed by Group II 50[18.3%] patients and Group IV 20[23.3%] patients p<0.019. In-hospital mortality was greater in Group IV than in any other group. Group IV patients were more frequently diabetic and hypertensive than patients in any other group. Group IV patients presented late to the hospital. There was no significant difference in site of myocardial infarction in different groups. Higher Killip class was observed in Group II and IV p<0.05. Streptokinase injection was given less frequently in Group IV than in any other group p <0.012. Only 34[39.5%] patients in Group IV had no complication during hospital stay while more patients in other groups had uneventful hospital stay. Female sex is associated with higher in-hospital mortality in older age group as compared to the male patients of same age group. p<0.001

Bochdalek hernia in adulthood: a case report and review of recent literature.

A 37-year-old Filipino woman presented with a post road-traffic accident fracture of dorsal spine 12. Chest radiograph revealed evidence of loops of small bowel in the left lung field. She admitted to symptoms of respiratory insufficiency since birth and treatment for tuberculosis in childhood. A pre-operative diagnosis of left traumatic diaphragmatic hernia was not confirmed at laparotomy which revealed typical left congenital Bochdalek hernia with smooth edges and herniation of small bowel and spleen into the left pleural cavity. Following reduction and repair of the hernia, the patient made an uneventful recovery. Chest radiograph remains normal till now, eight years post-operatively.

Diffuse pulmonary calcinosis and multiple soft tissue calcification in renal failure patient with pathological femoral fracture.

The rare occurrence of diffuse pulmonary calcinosis is described with case illustration of a patient who presented with a pathological femoral fracture during end-stage renal failure. Associated metastatic soft tissue calcification with parathyroid hyperplasia requiring parathyroidectomy was observed. Roentgenologic evidence of hyperparathyroidism with osteitis fibrosa cystica and a high product of the calcium and phosphate values were indications for the parathyroidectomy. Recent literature review of pulmonary calcinosis and multiple soft tissue calcification is also presented.

Value of clinical features in the diagnosis of enteric fever.

There is no objective data on the value of individual clinical symptoms or signs in the diagnosis of enteric fever in a febrile patient. The purpose of the study was to assess the value of some clinical and simple laboratory features in the diagnosis of enteric fever. One hundred & six patients with microbiologically confirmed enteric fever and 170 patients with other established febrile illnesses were included in the evaluation. History of stepladder pattern of rise of temperature, loose motions, relative bradycardia and coated tongue proved to be powerful markers of enteric fever with high specificity (100%, 94.71%, 94.71%, 94.12% respectively), positive and negative predictive values. Headache, hepatomegaly and splenomegaly were moderately powerful. ESR and WBC count appeared to have little value in the diagnosis of enteric fever. Pattern of onset and loose motions did not discriminate between typhoid and paratyphoid fever. Most of these patients had illness persisting beyond one week by which viral infections and infectious enterocolitides were largely excluded. Elucidation of power of these markers in distinguishing enteric fever from other febrile illnesses with the help of better designed prospective studies would lessen our dependence on expensive and time consuming laboratory investigations.

Vitamin D resistant rickets in children

Vitamin D resistant rickets is caused by a variety of heritable and acquired conditions. Thus Corm of rickets is a real diagnostic and therapeutic challenge. To find out the pattern of the different types of vitamin D resistant rickets, a study was conducted in the Department of Pediatrics. Postgraduate Medical Institute Lahore and Lahore General Hospital, Lahore for a period of one year from 1st August 1994 to 31st July 1995. A total of 30 children who fulfilled the criteria for vitamin D resistance were included in the study. All the patients were evaluated in detail. The patient's ages ranged from 0.25 to 12 years [Median age 2.7 years]. Most of the cases were seen between I-5 years wish male to female ratio of 1:1.14. About 70% of the patients fell in category of heritable conditions such as familial hypophosphatemia [26.66%], vitamin D dependent rickets type 1 [13.33%] and VDDR-II [6.66%], renal tubular acidosis [13.33%], Bartter syndrome [6.66%] and Fanconi syndrome [3.33%]. The acquired conditions seen were renal osteodystrophy [16.66%], rickets due to malabsorption [6.66%], rickets related to anticonvulsants [3.33%] and prematurity [3.33%]. In boys, the commonest cause was familial hypophosphatemia [35.71%] followed by renal osteodystrophy [17.64%]. In girls the commonest cause was vitamin D dependent rickets type I [25%] followed by familial hypophosphatemia [18.75%]. Most of the patients had marked stunting and skeletal deformities. The response to treatment was encouraging in many cases but was poor in renal osteodystrophy and vitamin D dependent rickets type II

A study of prolonged pyrexia in Dhaka.

In a prospective study conducted in the Institute of Postgraduate Medicine & Research (IPGMR), Dhaka, 212 patients with prolonged pyrexia were thoroughly evaluated clinically and with the help of laboratory investigations with a view to reaching the diagnosis. Their clinical and laboratory data were recorded. Clinical features pertaining to a particular organ gave appropriate clue in 52% cases. Imaging techniques were instrumental in 24%, microbiological or serological investigations in 35%, invasive procedures were diagnostic in 42%, laparotomy had to be resorted to in five cases. Infectious diseases were the commonest causes of prolonged pyrexia accounting for about 63.21% of cases followed by neoplasms (12.74%) and connective tissue disorders (10.85%). Tuberculosis was the most common infection (24.53% of all cases) followed by enteric fever (12.74%) and visceral leishmaniasis (9.43%). Pleura was the commonest seat for tuberculosis followed by lymph nodes and abdomen. Leukemias were the commonest neoplasm and SLE the commonest connective tissue disorder presenting with prolonged fever. Several fundamental observations were made in the study. Infections are the commonest cause of prolonged fever in our community, neoplasms and connective tissue disorders are also not rare. Secondly, patients with temperature between 100 to 101 degrees F should not be denied evaluation with the apprehension of unnecessarily investigating for habitual hyperthermia, as the condition was distinctly rare in the series. Thirdly, analysis of materials from organs or systems suspected to be abnormal clinically or by simple imaging techniques had high diagnostic yield. Finally, usual causes of prolonged fever are illnesses ordinarily encountered in clinical practice, pyrexia becomes protracted either because the presentation is atypical or incomplete, or because we fail to make proper use of available clinical or paraclinical information.