A Rapidly Enlarging Neck Mass: A Case Report.

Am J Med. 2019 12;132(12):e858-e859

Authors: Moale A, Zimmerman J

PMID: 31326410 [PubMed - indexed for MEDLINE]

Development of Autoimmune Interstitial Lung Disease in a Patient with Inclusion Body Myositis.

Am J Med. 2019 12;132(12):e854-e855

Authors: He C, Lee JS, Cool CD, Wicklund MP, Fischer A

PMID: 31310746 [PubMed - indexed for MEDLINE]

Predicting disease-causing variant combinations.

Proc Natl Acad Sci U S A. 2019 06 11;116(24):11878-11887

Authors: Papadimitriou S, Gazzo A, Versbraegen N, Nachtegael C, Aerts J, Moreau Y, Van Dooren S, Nowé A, Smits G, Lenaerts T

Abstract
Notwithstanding important advances in the context of single-variant pathogenicity identification, novel breakthroughs in discerning the origins of many rare diseases require methods able to identify more complex genetic models. We present here the Variant Combinations Pathogenicity Predictor (VarCoPP), a machine-learning approach that identifies pathogenic variant combinations in gene pairs (called digenic or bilocus variant combinations). We show that the results produced by this method are highly accurate and precise, an efficacy that is endorsed when validating the method on recently published independent disease-causing data. Confidence labels of 95% and 99% are identified, representing the probability of a bilocus combination being a true pathogenic result, providing geneticists with rational markers to evaluate the most relevant pathogenic combinations and limit the search space and time. Finally, the VarCoPP has been designed to act as an interpretable method that can provide explanations on why a bilocus combination is predicted as pathogenic and which biological information is important for that prediction. This work provides an important step toward the genetic understanding of rare diseases, paving the way to clinical knowledge and improved patient care.

PMID: 31127050 [PubMed - indexed for MEDLINE]

A local case of fulminant primary amoebic meningoencephalitis due to Naegleria fowleri.

Rural Remote Health. 2019 04;19(2):4313

Authors: McLaughlin A, O'Gorman T

Abstract
Primary amoebic meningoencephalitis is an extremely rare, predominantly fulminant central nervous system infection caused by the amoeba Naegleria fowleri, first described in Australia in 1965. Despite the ubiquitous presence of N. fowleri, as few as 300 cases of infection have since been reported worldwide, with a case fatality rate approaching 98%. A combination of low index of suspicion, non-specific clinical findings and largely ineffective treatment modalities make this rapidly progressive meningoencephalitis virtually impossible to treat. Early and aggressive treatment utilising intravenous and intrathecal routes by a multidisciplinary team of neurosurgeons, intensivists and microbiologists is required. Presented is a case of a 56-year-old man who presented to the Gold Coast University Hospital in Queensland, Australia, with rapidly progressive primary amoebic meningoencephalitis. He received maximal therapy and died of his disease while in hospital.

PMID: 30961348 [PubMed - indexed for MEDLINE]

Death of a Fetus With Myeloproliferative Disorder and Trisomy 21.

J Am Osteopath Assoc. 2019 Mar 01;119(3):208-211

Authors: Prentice D, Deiter R, Stanley J

Abstract
A 27-year-old woman, gravida 2, para 1, presented at 24 weeks gestation with an intrauterine death. She previously consulted with maternal-fetal medicine because of a high suspicion of trisomy 21 after abnormal maternal serum screen and cell-free DNA test results. The patient elected to have chromosomal analysis following the death of the fetus, which confirmed a trisomy 21 diagnosis. Placental pathologic findings suggested that the cause of fetal death was total occlusion of the major vessels due to the accumulation of myeloid precursor cells, a novel mechanism. This case report discusses the rare finding of myeloproliferative disorder as a cause of death of a fetus with trisomy 21.

PMID: 30801117 [PubMed - indexed for MEDLINE]

Translational science: Newly emerging science in biology and medicine - Lessons from translational research on the natriuretic peptide family and leptin.

Proc Jpn Acad Ser B Phys Biol Sci. 2019;95(9):538-567

Authors: Nakao K

Abstract
Translation is the process of turning observations in the laboratory, clinic, and community into interventions that improve the health of individuals and the public, ranging from diagnostics and therapeutics to medical procedures and behavioral changes. Translational research is defined as the effort to traverse a particular step of the translation process for a particular target or disease. Translational science is a newly emerging science, distinct from basic and clinical sciences in biology and medicine, and is a field of investigation focused on understanding the scientific and operational principles underlying each step of the translational process. Advances in translational science will increase the efficacy and safety of translational research in all diagnostic and therapeutic areas. This report examines translational research on novel hormones, the natriuretic peptide family and leptin, which have achieved clinical applications or for which studies are still ongoing, and also emphasizes the lessons that translational science has learned from more than 30 years' experience in translational research.

PMID: 31708497 [PubMed - indexed for MEDLINE]

ACUTE BURIED BUMPER SYNDROME: A RARE ENTITY.

Gastroenterol Nurs. 2019 Jul/Aug;42(4):388-390

Authors: Olmez S, Sarıtaş B, Nar H, Tas A, Kara B

PMID: 31365427 [PubMed - indexed for MEDLINE]

Intravitreal Ranibizumab for the Treatment of Visual Impairment Due to Choroidal Neovascularization Associated with Rare Diseases: Cost-Effectiveness in the UK.

Adv Ther. 2019 03;36(3):632-644

Authors: McCarthy G, Fenu E, Bennett N, Almond C

Abstract
INTRODUCTION: This study sought to determine the cost-effectiveness of intravitreal ranibizumab compared with best supportive care (BSC; considered to be no active treatment) for the treatment of visual impairment due to choroidal neovascularization (CNV) associated with causes other than neovascular age-related macular degeneration (nAMD) and pathologic myopia (PM) in a UK setting.
METHODS: An individual patient-level simulation model was developed to estimate the lifetime costs and quality-adjusted life years (QALYs) of ranibizumab vs. BSC. Regression analyses, performed on patient-level data collected within the pivotal phase III MINERVA trial, modelled visual acuity (VA) progression while patients remained on treatment. Patient utilities were modelled as a function of VA in both eyes and resource use estimates were based on trial data or the literature. Costs were evaluated from the perspective of the UK National Health Service and personal social services, with future costs and health outcomes discounted at 3.5% per annum. Sensitivity and scenario analyses were conducted.
RESULTS: The incremental cost-effectiveness ratio for intravitreal ranibizumab was £1363 per QALY compared to BSC and was associated with an incremental benefit of 1.06 QALYs and an incremental cost of £1444 per patient. Drug and administration costs of intravitreal ranibizumab were offset by the prevention of the development of blindness and its associated costs, while the increase in benefits was driven by a reduction in mortality risk and an improved health-related quality of life attributed to an improvement in VA. The findings were robust to a range of sensitivity analyses and ranibizumab consistently remained cost-effective at a willingness-to-pay threshold of £20,000-30,000 per QALY gained for all sensitivity analyses.
CONCLUSION: Intravitreal ranibizumab is a highly cost-effective intervention for the treatment of CNV due to causes other than nAMD and PM as it delivers substantial QALY gains to patients while making cost savings vs. BSC.
FUNDING: Novartis Pharmaceuticals UK Ltd.

PMID: 30726549 [PubMed - indexed for MEDLINE]

Entry Into New Therapeutic Areas: The Effect of Alliance on Clinical Trials.

Ther Innov Regul Sci. 2019 09;53(5):648-653

Authors: Okada K, Sengoku S

Abstract
BACKGROUND: Entry into a new therapeutic area, that is, one in which a pharmaceutical firm lacks experience, is a considerable challenge for firms that need to overcome scientific and technological barriers. To address this issue, the present study aims to explore the potentiality of alliances in an empirical manner.
METHODS: From the clinical trials sponsored by 20 major pharmaceutical firms during 2008-2016 listed at ClinicalTrials.gov (n = 14,941 clinical trials), cases of entering a new therapeutic area for a pharmaceutical firm were extracted (n = 73), followed by statistical analyses to evaluate the effect of alliances in this regard.
RESULTS: We found that the average number of participating organizations in the cases of entering a new therapeutic area was significantly larger than that in the cases of entering an area in which firms had experience (P < .01), suggesting that alliance has a positive effect on new therapeutic entry for these pharmaceutical firms. Second, we found that the cases of partnering with nonindustrial or nongovernmental organizations (ie, universities, research institutes, hospitals, funding agencies, and others; n = 32 of the 73) were significantly associated with these new entry trials (adjusted odds ratio = 1.1, P < .05). Furthermore, we identified that 10 of the 32 clinical trials were associated with rare diseases, which is an overrepresentation compared to the occurrence in the universe (1015 of the 14,941; P < 10-5).
CONCLUSIONS: These findings strongly suggest the importance of alliances with diversified partners in new therapeutic entry and also provide a basis for further detailed investigation of key success factors for pharmaceutical firms.

PMID: 30428715 [PubMed - indexed for MEDLINE]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

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Adult Langerhans cell histiocytosis: An unusual cause of referred knee pain.

Malays Fam Physician. 2019;14(3):60-64

Authors: Swarna Nantha Y, Yeoh MH, Sharif SM

Abstract
Langerhans cell histiocytosis (LCH) in adults is rare and regarded as an 'orphan disease.' The systemic symptoms of LCH can mimic many other undifferentiated diseases seen at the primary care level. Failure to diagnose and delays in referral are common pitfalls in the management of this disease. We present a case of a 34-year-old woman with referred knee pain who was eventually diagnosed with multi-system LCH 4 years after the initial presentation. The mean age of presentation of LCH symptoms in adults is 33. Bone lesions are the frequent presentation of LCH in this age group. Endocrine involvement in LCH is seen in the form of diabetes insipidus (DI), which remains the most common extraskeletal presentation of LCH in adults. In the case discussed here, a definitive diagnosis of LCH was established through tissue biopsy. The spectrum of undifferentiated symptoms underscores the difficulty and delay in making a diagnosis associated with the condition. Most GPs not only face the predicament of initial recognition but also fail to merge presenting symptoms to form a purposeful referral of this elusive disease to a tertiary care unit.

PMID: 32175042 [PubMed]

Disease awareness or subtle product placement? Orphan diseases featured in the television series "House, M.D." - a cross-sectional analysis.

BMC Med Ethics. 2020 Mar 14;21(1):20

Authors: Mechler K, Rausch J, Mountford WK, Ries M

Abstract
BACKGROUND: Approximately 7% of the general population is affected by an orphan disease, which, in the United States, is defined as affecting fewer than 1 in 1500 people. Disease awareness is often low and time-to-diagnosis delayed. Different legislations worldwide have created incentives for pharmaceutical companies to develop drugs for orphan diseases. A journalistic article in Bloomberg Businessweek has claimed that pharmaceutical companies have tried marketing orphan drugs by placing a specific disease into the popular television series "House, M.D." which features diagnostic journeys and was produced between 2004 and 2012. This study aimed to describe the presentation of orphan diseases in the television series "House, M.D.", to test in an exploratory fashion the hypothesis that treatable orphan conditions are overrepresented in "House, M.D." and to discuss whether such marketing practices may or may not be ethical.
METHODS: A list of all medical cases depicted in the television series "House, M.D." was obtained and classified as orphan or non-orphan according to the Orphanet database. The ratios of orphan diseases among all diseases, such with an orphan drug designation and such with an orphan drug approval by the FDA were then compared with conservative approximations of real world conditions (chi-squared tests for equality of proportions). STROBE criteria were respected.
RESULTS: Out of a total of n = 181 different medical diagnoses, n = 42 (23.2%) were orphan diseases. The difference in percentages in between "House, M.D." and reality was not statistically significant for orphan diseases overall (p = 0.96), yet was statistically significantly higher for both orphan diseases with one or more orphan drug designations (p = 0.0192) and such with one or more approved orphan drugs (p < 0.0001).
CONCLUSIONS: Orphan diseases with a designated and/or approved orphan drug were overrepresented in the television series "House, M.D." with statistical significance while orphan diseases overall were not. This may be explained by (so far) undocumented efforts of pharmaceutical companies to place their orphan drugs in the television series, as described in the article in Bloomberg Businessweek. Further research is needed into marketing practices in popular and emerging media formats.

PMID: 32171294 [PubMed - in process]

A tailored approach to fusion transcript identification increases diagnosis of rare inherited disease.

PLoS One. 2019;14(10):e0223337

Authors: Oliver GR, Tang X, Schultz-Rogers LE, Vidal-Folch N, Jenkinson WG, Schwab TL, Gaonkar K, Cousin MA, Nair A, Basu S, Chanana P, Oglesbee D, Klee EW

Abstract
BACKGROUND: RNA sequencing has been proposed as a means of increasing diagnostic rates in studies of undiagnosed rare inherited disease. Recent studies have reported diagnostic improvements in the range of 7.5-35% by profiling splicing, gene expression quantification and allele specific expression. To-date however, no study has systematically assessed the presence of gene-fusion transcripts in cases of germline disease. Fusion transcripts are routinely identified in cancer studies and are increasingly recognized as having diagnostic, prognostic or therapeutic relevance. Isolated reports exist of fusion transcripts being detected in cases of developmental and neurological phenotypes, and thus, systematic application of fusion detection to germline conditions may further increase diagnostic rates. However, current fusion detection methods are unsuited to the investigation of germline disease due to performance biases arising from their development using tumor, cell-line or in-silico data.
METHODS: We describe a tailored approach to fusion candidate identification and prioritization in a cohort of 47 undiagnosed, suspected inherited disease patients. We modify an existing fusion transcript detection algorithm by eliminating its cell line-derived filtering steps, and instead, prioritize candidates using a custom workflow that integrates genomic and transcriptomic sequence alignment, biological and technical annotations, customized categorization logic, and phenotypic prioritization.
RESULTS: We demonstrate that our approach to fusion transcript identification and prioritization detects genuine fusion events excluded by standard analyses and efficiently removes phenotypically unimportant candidates and false positive events, resulting in a reduced candidate list enriched for events with potential phenotypic relevance. We describe the successful genetic resolution of two previously undiagnosed disease cases through the detection of pathogenic fusion transcripts. Furthermore, we report the experimental validation of five additional cases of fusion transcripts with potential phenotypic relevance.
CONCLUSIONS: The approach we describe can be implemented to enable the detection of phenotypically relevant fusion transcripts in studies of rare inherited disease. Fusion transcript detection has the potential to increase diagnostic rates in rare inherited disease and should be included in RNA-based analytical pipelines aimed at genetic diagnosis.

PMID: 31577830 [PubMed - indexed for MEDLINE]

Two case reports of telangiectasia macularis multiplex acquisita.

Int J Dermatol. 2019 Nov;58(11):1334-1336

Authors: Zhao S, Wang X, Pan M, Lin X, Zhu X

PMID: 30315565 [PubMed - indexed for MEDLINE]

Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington's disease.

BMC Neurol. 2020 Mar 12;20(1):87

Authors: Ratna N, Kamble NL, Venkatesh SD, Purushottam M, Pal PK, Jain S

Abstract
BACKGROUND: Huntington's disease (HD), an inherited, often late-onset, neurodegenerative disorder, is considered to be a rare, orphan disease. Research into its genetic correlates and services for those affected are inadequate in most low-middle income countries, including India. The apparent 'incurability' often deters symptomatic and rehabilitative care, resulting in poor quality of life and sub-optimal outcomes. There are no studies assessing disease burden and outcomes from India.
METHODS: We attempted to evaluate individuals diagnosed to have HD at our tertiary-care center between 2013 and 2016 for clinical symptoms, functionality, mortality, follow up status through a structured interview, clinical data from medical records and UHDRS-TFC scoring.
RESULTS: Of the 144 patients, 25% were untraceable, and another 17 (11.8%) had already died. Mean age at death and duration of illness at the time of death, were 53 years and 7 years respectively, perhaps due to suicides and other comorbidities at an early age. The patients who could be contacted (n = 81) were assessed for morbidity and total functional capacity (TFC). Mean CAG repeat length and TFC score were 44.2 and 7.5 respectively. Most individuals (66%) were in TFC stage I and II and could perhaps benefit from several interventions. The TFC score correlated inversely with duration of illness (p < 0.0001). The majority were being taken care of at home, irrespective of the physical and mental disability. There was a high prevalence of psychiatric morbidity (91%) including suicidal tendency (22%). Three of the 17 who died had committed suicide, and several other families reported suicidal history in other family members. Only about half the patients (57%) maintained a regular clinical follow-up.
CONCLUSIONS: This study demonstrates the poor follow-up rates, significant suicidality and other psychiatric symptoms, sub-optimal survival durations and functional outcomes highlighting the need for holistic care for the majority who appear to be amenable to interventions.

PMID: 32164608 [PubMed - in process]

Clinical presentation, treatment modalities and outcome in patients with adrenocortical carcinoma: A single center experience.

Neoplasma. 2020 Jan;67(1):209-213

Authors: Bronswijk MJH, Laenen A, Bechter OE

Abstract
Adrenocortical carcinoma is an orphan disease usually associated with a poor prognosis. Surgery is the only treatment with a curative intent, leaving systemic therapy mainly for the purpose of symptom control. First line combination chemotherapy with Etoposide, Doxorubicin, Cisplatin and Mitotane (EDP-Mitotane) is considered the standard of care, although this regimen is not associated with an overall survival benefit. Due to the rarity of the disease no standard therapy exists in the second line or when patients are intolerant to the first line treatment. Therefore, treatment of these patients is usually following a very individual path in daily practice. Our aim was to retrospectively analyze treatment of patients with adrenocortical carcinoma in our tertiary center and compare treatment outcomes with reports in the literature. Our findings reflect the daily practice in adrenocortical carcinoma treatment and showed that surgery is the mainstay of therapy, even in some cases with metastatic disease. Adjuvant therapy in adrenocortical carcinoma was initiated less frequently than suggested by current guidelines. Furthermore, most of the patients in our cohort received more than one line of chemotherapy for metastatic or inoperable disease with overall survival rates comparable to those published. In summary, our analysis stresses the importance of clinical trial activity in this rare disease in order to standardize and improve adrenocortical carcinoma therapy more profoundly.

PMID: 31777255 [PubMed - indexed for MEDLINE]

A case of pyoderma gangrenosum induced by insulin.

Int Wound J. 2019 Oct;16(5):1239-1242

Authors: Noronha M, Arora S, Pai K, Sathish Pai B, Jindal A

Abstract
Pyoderma gangrenosum (PG) is a rare auto-inflammatory, neutrophilic, ulcerative disorder characterised by acutely painful, rapidly spreading, sterile ulcers over the trunk and lower limbs. The pathogenic mechansim of PG is under constant evolution and drugs are emerging to be a an important trigger. In the literature, 52 cases of drug-induced PG have been documented, of which cocaine laced with levamisole has shown most direct association, with a mean Naranjo score of 9. Other drugs probably associated with PG are isotretinoin, sunitinib, and propylthiouracil. We describe a case of a 59-year-old male who had multiple well-defined ulcers with a violaceous, undermined edge limited to the site of subcutaneous injection of insulin. Histopathological examination showed psoriasiform hyperplasia in the epidermis, with abundant infiltration of neutrophils in the dermis, consistent with the clinical diagnosis of PG. As per the modified Naranjo algorithm, the patient's total score was 7, indicating insulin to be the probable causative agent in our case. So, compiling temporal localisation of lesions to the site of administration of insulin and clinical, histopathological, and Naranjo score evidence all prompt the diagnosis of PG. Insulin stimulates the release of matrix-metalloproteinases 9 which acts as endopeptidases and also results in the chemotaxis of neutrophils, causing ulcer formation. This is the first case reporting PG triggered by insulin.

PMID: 31353778 [PubMed - indexed for MEDLINE]

Common pre-diagnostic features in individuals with different rare diseases represent a key for diagnostic support with computerized pattern recognition?

PLoS One. 2019;14(10):e0222637

Authors: Grigull L, Mehmecke S, Rother AK, Blöß S, Klemann C, Schumacher U, Mücke U, Kortum X, Lechner W, Klawonn F

Abstract
BACKGROUND: Rare diseases (RD) result in a wide variety of clinical presentations, and this creates a significant diagnostic challenge for health care professionals. We hypothesized that there exist a set of consistent and shared phenomena among all individuals affected by (different) RD during the time before diagnosis is established.
OBJECTIVE: We aimed to identify commonalities between different RD and developed a machine learning diagnostic support tool for RD.
METHODS: 20 interviews with affected individuals with different RD, focusing on the time period before their diagnosis, were performed and qualitatively analyzed. Out of these pre-diagnostic experiences, we distilled key phenomena and created a questionnaire which was then distributed among individuals with the established diagnosis of i.) RD, ii.) other common non-rare diseases (NRO) iii.) common chronic diseases (CD), iv.), or psychosomatic/somatoform disorders (PSY). Finally, four combined single machine learning methods and a fusion algorithm were used to distinguish the different answer patterns of the questionnaires.
RESULTS: The questionnaire contained 53 questions. A total sum of 1763 questionnaires (758 RD, 149 CD, 48 PSY, 200 NRO, 34 healthy individuals and 574 not evaluable questionnaires) were collected. Based on 3 independent data sets the 10-fold stratified cross-validation method for the answer-pattern recognition resulted in sensitivity values of 88.9% to detect the answer pattern of a RD, 86.6% for NRO, 87.7% for CD and 84.2% for PSY.
CONCLUSION: Despite the great diversity in presentation and pathogenesis of each RD, patients with RD share surprisingly similar pre-diagnosis experiences. Our questionnaire and data-mining based approach successfully detected unique patterns in groups of individuals affected by a broad range of different rare diseases. Therefore, these results indicate distinct patterns that may be used for diagnostic support in RD.

PMID: 31600214 [PubMed - indexed for MEDLINE]

A New Era for Rare Genetic Diseases: Messenger RNA Therapy.

Hum Gene Ther. 2019 10;30(10):1180-1189

Authors: Martini PGV, Guey LT

Abstract
Exogenous delivery of messenger RNA (mRNA) is emerging as a new class of medicine with broad applicability including the potential to treat rare monogenic disorders. Recent advances in mRNA technology, including modifications to the mRNA itself along with improvements to the delivery vehicle, have transformed the utility of mRNA as a potential therapy to restore or replace different types of therapeutic proteins. Preclinical proof-of-concept has been demonstrated for mRNA therapy for three different rare metabolic disorders: methylmalonic acidemia, acute intermittent porphyria, and Fabry disease. Herein, we review those preclinical efficacy and safety studies in multiple animal models. For all three disorders, mRNA therapy restored functional protein to therapeutically relevant levels in target organs, led to sustained and reproducible pharmacology following each dose administration of mRNA, and was well tolerated as supported by liver function tests evaluated in animal models including nonhuman primates. These data provide compelling support for the clinical development of mRNA therapy as a treatment for various rare metabolic disorders.

PMID: 31179759 [PubMed - indexed for MEDLINE]

Knockin mouse model of the human CFL2 p.A35T mutation results in a unique splicing defect and severe myopathy phenotype.

Hum Mol Genet. 2020 Mar 11;:

Authors: Rosen SM, Joshi M, Hitt T, Beggs AH, Agrawal PB

Abstract
Cofilin-2 is an actin-binding protein that is predominantly expressed in skeletal and cardiac muscles and belongs to the AC group of proteins which includes cofilin-1 and destrin. In humans, cofilin-2 (CFL2) mutations have been associated with congenital myopathies that include nemaline and myofibrillar myopathy. To understand the pathogenicity of the human CFL2 mutation, p.A35T, that first linked cofilin-2 with the human disease, we created a knock-in mouse model. The Cfl2A35T/A35T (KI) mouse were indistinguishable from their wild-type littermates at birth, but they rapidly worsened and died by postnatal day 9. The phenotypic, histopathologic and molecular findings mimicked the constitutive Cfl2-knockout (KO) mice described previously, including sarcomeric disruption and actin accumulations in skeletal muscles and negligible amounts of cofilin-2 protein. In addition, KI mice demonstrated a marked reduction in Cfl2 mRNA levels in various tissues including skeletal muscles. Further investigation revealed evidence of alternative splicing with the presence of two alternate transcripts of smaller size. These alternate transcripts were expressed at very low levels in the wild-type mice and were significantly upregulated in the mutant mice, indicating that pre-translational splicing defects may be a critical component of the disease mechanism associated with the mutation. Evidence of reduced expression of the full-length CFL2 transcript was also observed in the muscle biopsy sample of the patient with p.A35T mutation.

PMID: 32160286 [PubMed - as supplied by publisher]