Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Fever as a predictor of adverse outcomes in COVID-19.

BACKGROUND/INTRODUCTION: There are little data on outcomes of COVID-19 patients with the presence of fever compared to the presence of symptoms. AIM: We examined the associations between symptomology, presence of fever and outcomes of a COVID-19 cohort. DESIGN AND METHODS: Between 23 January and 30 April 2020, 554 COVID-19 patients were admitted to a tertiary hospital in Singapore. They were allocated into four groups based on symptomology and fever-Group 1: asymptomatic and afebrile, Group 2: symptomatic but afebrile, Group 3: febrile but asymptomatic and Group 4: symptomatic and febrile. The primary outcomes were intensive care unit (ICU) admissions and mortality. The composite end-point included ICU admissions, mortality or any COVID-19 related end-organ involvement. RESULTS: There were differences in ferritin (P=0.003), C-reactive protein (CRP) levels (P<0.001) and lymphopenia (P=0.033) across all groups, with the most favourable biochemical profile in Group 1, and the least in Group 4. Symptomatic groups (Groups 2 and 4) had higher ICU admissions (1.9% and 6.0%, respectively, P=0.003) than asymptomatic groups (Groups 1 and 3). Composite end-point was highest in Group 4 (24.0%), followed by Group 3 (8.6%), Group 2 (4.8%) and Group 1 (2.4%) (P<0.001). The presence of fever (OR 4.096, 95% CI 1.737-9.656, P=0.001) was associated with the composite end-point after adjusting for age, pulse rate, comorbidities, lymphocyte, ferritin and CRP. Presence of symptoms was not associated with the composite end-point. DISCUSSION/CONCLUSION: In this COVID-19 cohort, presence of fever was a predictor of adverse outcomes. This has implications on the management of febrile but asymptomatic COVID-19 patients.

Rapid publications risk the integrity of science in the era of COVID-19.

BACKGROUND: Preprint manuscripts, rapid publications and opinion pieces have been essential in permitting the lay press and public health authorities to preview data relating to coronavirus disease 2019 (COVID-19), including the range of clinical manifestations and the basic epidemiology early on in the pandemic. However, the rapid dissemination of information has highlighted some issues with communication of scientific results and opinions in this time of heightened sensitivity and global concern. MAIN TEXT: Rapid publication of COVID-19 literature through expedited review, preprint publications and opinion pieces are important resources for the medical scientific community. Yet the risks of unverified information loom large in times when the healthcare community is desperate for information. Information that has not been properly vetted, or opinion pieces without solid evidence, may be used to influence public health policy decisions. We discuss three examples of unverified information and the consequences in this time of high anxiety surrounding COVID-19. CONCLUSIONS: In an era when information can be widely and swiftly disseminated, it is important to ensure that the scientific community is not an inadvertent source of misinformation. This will require a multimodal approach, with buy-in from editors, publishers, preprint servers, authors and journalists. The landscape of medical publications has changed, and a collaborative approach is required to maintain a high standard of scientific communications.

Joint 24th Medicines for Europe and 21st International Generic and Biosimilars Association (IGBA) Annual Conference (June 13-15, 2018 - Budapest, Hungary).

The joint 24th Medicines for Europe and 21st International Generic and Biosimilars Association (IGBA) Annual Conference brought together key industry leaders and more than 200 participants in Budapest, Hungary, to discuss both challenges and opportunities for the global generic, biosimilar and value added medicines industries. Challenges relating to sustainability were debated with key experts, who shared perspectives on topics such as medicines shortages, use of data, Brexit, international regulatory cooperation, the E.U. Falsified Medicines Directive (FMD) and the potential impact of antimicrobial resistance. European industry leaders outlined the period of intense preparations needed to ensure compliance by the early 2019 milestones for the FMD and Brexit. The conference also anticipated exciting opportunities for the industry and broadly welcomed the European Commission's legislative proposal for a (long-awaited and much discussed) E.U. Supplementary Protection Certificate manufacturing waiver. Medicines for Europe and IGBA are committed to supporting and strengthening such policy initiatives aimed at boosting European competitiveness, increasing investments in R+D for biosimilar medicines, and most importantly, delivering faster access to medicines for patients. The importance of not forgetting that the ultimate aim of the industry was to facilitate patient access to necessary medicines was stressed throughout the conference. As the conference took place in Hungary, László György (State Secretary for Economic Strategy and Regulation at the Ministry of Innovation and Technology) spoke about the role of technology innovation and access to medicines in the country and the role of his ministry. He indicated that the primary goal of the newly established ministry was to maintain and improve decent living conditions in the light of aging populations and enhance the competitiveness of the pharmaceutical industry, "which plays a decisive role in the Hungarian economy."

Preliminary investigation of urine N-telopeptide concentration as a biomarker of bone resorption in dogs receiving glucocorticoids.

OBJECTIVES: The influence of glucocorticoid therapy on bone resorption in dogs using a urine N-telopeptide assay was investigated. MATERIALS AND METHODS: Thirty-one dogs receiving oral glucocorticoids and 31 age-matched healthy control dogs were enrolled. Urine N-telopeptide concentration was measured using a commercially available immunoassay and results were expressed as a ratio against urinary creatinine concentration. Dogs receiving glucocorticoids were divided into three subgroups based on daily glucocorticoid dose and three subgroups based on treatment duration. Urine N-telopeptide concentration was then compared between groups. RESULTS: Urine N-telopeptide concentration was significantly higher in dogs receiving glucocorticoids compared to the control group. CLINICAL SIGNIFICANCE: This preliminary study demonstrates significant increase in urine N-telopeptide concentration in dogs receiving glucocorticoid therapy compared to control dogs. Further studies are needed to assess whether this increase in urine N-telopeptide concentration correlates with decreases in bone mineral density as has been identified in humans.

Measurement of serum 7α-hydroxy-4-cholesten-3-one as a marker of bile acid malabsorption in dogs with chronic diarrhoea: a pilot study.

Bile acid malabsorption is a common cause of chronic diarrhoea in people, however it has never previously been investigated in dogs, despite clinical suspicion of its existence. The goal of this study was to assess the feasibility of measuring serum 7α-hydroxy-4-cholesten-3-one (C4) in dogs, as a potential marker of bile acid malabsorption, and to see whether this is related to clinical disease severity or the presence of hypocobalaminaemia. Serum C4 concentration was measured in 20 clinically healthy control dogs and 17 dogs with chronic diarrhoea. Three of the 17 affected dogs (17.6 per cent) had a C4 concentration significantly above the range of clinically healthy dogs; these dogs were all poorly responsive to conventional therapy. These results suggest that bile acid malabsorption may be a clinically relevant disorder in dogs with chronic diarrhoea and serum C4 may be a useful tool to investigate this further.

The epidemiology of sepsis during rapid response team reviews in a teaching hospital.

In a three-month retrospective study, we assessed the proportion of rapid response team (RRT) calls associated with systemic inflammatory response syndrome (SIRS) and sepsis. We also documented the site of infection (whether it was community- or hospital-acquired), antibiotic modifications after the call and in-hospital outcomes. Amongst 358 RRT calls, two or more SIRS criteria were present in 277 (77.4%). Amongst the 277 RRT calls with SIRS criteria, 159 (57.4%) fulfilled sepsis criteria in the 24 hours before and 12 hours after the call. There were 118 of 277 (42.6%) calls with SIRS criteria but no evidence of sepsis and 62 of 277 (22.3%) calls associated with both criteria for sepsis as well as an alternative cause for SIRS. Hence, 159 (44.4%) of all 358 RRT calls over the three-month study period fulfilled criteria for sepsis and in 97 (159-62) (27.1%) of the 358 calls, there were criteria for sepsis without other causes for SIRS criteria. The most common sites of infection were respiratory tract (86), abdominal cavity (38), urinary tract (26) and bloodstream (26). Infection was hospital-acquired in 91 (57.2%) and community-acquired in 67 (42.1%) cases, respectively. Patients were on antibiotics in 127 of 159 (79.9%) cases before the RRT call and antibiotics were added or modified in 76 of 159 (47.8%) cases after RRT review. The hospital length-of-stay of patients who received an RRT call associated with sepsis was longer than those who did not (16.0 [8.0 to 28.5] versus 10 days [6.0 to 18.0]; P=0.002).

Partial trisomy 3p24.3 and partial monosomy 5p15.33: case report and a literature review.

We report on a preterm neonate with a deletion of the distal short arm of chromosome 5p15.33 and partial trisomy of the distal short arm of chromosome 3p24.3. The patient was the first-born monozygotic twin. There were no pertinent facial or physical features except a small lower lip hemangioma. The neonate presented with cardiac defects, which included a patent ductus arteriosus, an atrial septal defect and ventricular septal defects. After 94 days of age, however, the patient died from superior vena cava syndrome, recurrent chylothoraces and generalized anasarca. Array comparative genomic hybridization (aCGH) using a custom oligonucleotide microarray (Agilent 180,000 probe platform revealed a terminal duplication of 1,128 oligonucleotide probes from 3pter to 3p24.3, spanning approximately 20.4 megabases (Mb), and a terminal deletion of 271 oligonucleotide probes from 5pter to 5p15.33, spanning approximately 4.3 Mb. This is the first report of a patient with partial trisomy 3p24.3 and partial monosomy 5p15.33 without major dysmorphic features.

Extracorporeal shock wave treatment of non- or delayed union of proximal metatarsal fractures.

BACKGROUND: Nonunion or delayed union of fractures in the proximal aspect of metatarsals 1 to 4 and Zone 2 of the fifth metatarsal were treated by high energy extracorporeal shock wave treatment (ESWT) to study the safety and efficacy of this method of treatment in a FDA study of the Ossatron device. MATERIALS AND METHODS: In a prospective single-arm, multi-center study, 34 fractures were treated in 32 patients (two subjects had two independent fractures) with ESWT. All fractures were at least 10 (range, 10 to 833) weeks after injury, with a median of 23 weeks. ESWT application was conducted using a protocol totaling 2,000 shocks for a total energy application of approximately 0.22 to 0.51 mJ/mm2 per treatment. The mean ESWT application time for each of the treatments was 24.6 +/- 16.6 minutes, and anesthesia time averaged 27.1 +/- 10.4 minutes. All subjects were followed for 1 year after treatment at intervals of 12 weeks, 6, 9, and 12 months. RESULTS: The overall success rate at the 12-week visit was 71% with low complications, significant pain improvement as well as improvement on the SF-36. The success/fail criteria was evaluated again at the 6- and 12-month followup, showing treatment success rates of 89% (23/26) and 90% (18/20), respectively. The most common adverse event was swelling in the foot, reported by five subjects (15.6%). CONCLUSION: High-energy ESWT appears to be effective and safe in patients for treatment of nonunion or a delayed healing of a proximal metatarsal, and in fifth metatarsal fractures in Zone 2.

Understanding the optical spectroscopy of amphiphilic molecular rectifiers: a density functional approach.

We present results of first principles density functional theory calculations of the electronic and atomic structural properties of model Z-type Langmuir-Blodgett (LB) layers comprising amphiphilic quinolinium tricyanoquinodimethanide (Q3CNQ) chromophores. We find that the chromophore electronic ground state is not as clearly "zwitterionic" as required by models to explain electrical rectification purportedly seen in such systems. The computed visible region transitions are not what have been assumed to be the intervalence charge transfer bands seen in the visible region of molecules in Z-type LB films. Our own LB deposition and spectroscopic studies suggest that almost all visible region features previously seen may be ascribed to aggregates. The calculated lowest energy electronic excitation between HOMO and LUMO levels, which is located in the near infrared region, has a transition moment aligned approximately 9° off the molecular long axis, and has a normalized oscillator strength of 1 order of magnitude higher than those of the visible region transitions. This most dominant feature has been neglected from discussions of Langmuir-Blodgett layer rectification but our own deposition studies show no sign of this feature, indicating that the structure of the modeled system differs from that of typical experimental structures. The model indicates that such idealized LB layer structures cannot confidently be invoked to explain their experimental optical or electrical properties.

Estimation of total body water from bioelectrical impedance spectroscopy in oncology outpatients receiving radiotherapy and agreement with three prediction equations.

BACKGROUND: Bioelectrical impedance spectroscopy (BIS) may be more accurate in determining total body water (TBW) than bioelectrical impedance analysis (BIA). The present study compared the agreement between three TBW prediction equations developed using BIA and BIS-derived TBW in oncology outpatients. METHODS: A cross-sectional, observational study was conducted in 37 outpatients receiving radiotherapy (27 males/10 females, aged 68.3 +/- 10.2 years). TBW was estimated by BIS (TBW(BIS)) and three BIA TBW prediction equations (TBW(ca-u): underweight cancer patients; TBW(ca-n): normal-weight cancer patients; and TBW(rad): patients receiving radiotherapy). Bland-Altman analyses determined agreement between methods. BIS-derived TBW using new resistivity constants was calculated. RESULTS: The mean +/- SD of TBW estimated by BIS was 39.8 +/- 8.3 L, which was significantly different from the prediction equations; TBW(rad) 35.1 +/- 7.9 L, TBW(ca-u) 33.1 +/- 7.5 L and TBW(ca-n) 32.3 +/- 7.3 L, (P < 0.001). Using new resistivity constants, TBW was 36.2 +/- 8.1 L but this still differed from the equations (P < 0.001). Bias between TBW(BIS) and that predicted by the equations was in the range 4.7-7.4 L or 1.1-3.9 L using new resistivity constants. CONCLUSIONS: TBW estimated by BIS cannot be directly compared with oncology-specific BIA equations, suggesting that BIS cannot be used at the group level in outpatients receiving radiotherapy. There was a reduced bias with BIS using new resistivity constants; however, further research should determine any advantage of BIS over BIA in this population.

[Holt-Oram syndrome: characterization of a novel mutation]. / Síndrome de Holt-Oram: caracterización de una nueva mutación.

INTRODUCTION: Cardiomyelic syndromes encompass congenital heart disease and skeletal malformations of the upper limbs and are related to mutations in transcription factors with T-Box domains. Holt-Oram syndrome is caused by a dominant mutation in the TBX5 gene that alters the three-dimensional structure of the protein and its DNA binding function. Several point mutations and deletions in TBX5 have been reported in patients with the Holt-Oram syndrome phenotype. PATIENTS AND METHODS: The proband was a boy with a large atrial septal defect ostium secundum type and a ventricular septal defect, diagnosed by clinical findings (heart murmur) and echocardiography. He also presented slightly hypoplastic thumbs with distal bilateral placement and an implantation index of 0.19 (compared with an average of 0.50 for his gestational age at birth). The boy was referred to the department of medical genetics to rule out 22q11.2 microdeletion syndrome. RESULTS: Karyotype and fluorescence in situ hybridization at locus D22S75 were both normal. Because of his clinical findings, molecular study for Holt-Oram syndrome was indicated, leading to the finding of a mutation at intron 7 of TBX5, probably producing a splicing alteration of the gene and resulting in a protein truncated at its C-terminal end. The proband's parents presented the wild type sequence of the gene, thus indicating that the mutation was produced de novo, although a possible germinal mosaicism in the parents could not be ruled out. CONCLUSIONS: Holt-Oram syndrome is the most frequent cause of cardiomyelic syndrome. All children with heart malformations and abnormalities of the upper limbs such as absent, hypoplastic, distally placed or triphalangic thumbs should undergo molecular studies for this syndrome.

Síndrome de Holt-Oram: caracterización de una nueva mutación / Holt-Oram syndrome: characterization of a novel mutation

Introducción Los síndromes cardiomiélicos comprenden cardiopatías congénitas y malformaciones esqueléticas de los miembros superiores, y están relacionados con mutaciones deletéreas de factores de transcripción con dominios del tipo T-Box. El síndrome de Holt-Oram se debe a una mutación dominante en el gen TBX5 que altera la estructura tridimensional de la proteína impidiendo su correcta unión al ADN. Se han descrito varias mutaciones puntuales y deleciones de TBX5 en pacientes con fenotipo de síndrome de Holt-Oram. Pacientes y métodos El paciente es un niño con una comunicación interauricular (CIA) del tipo ostium secundum grande y una comunicación interventricular (CIV) diagnosticados por clínica (soplo) y ecocardiografía. Presenta además unos dedos pulgares algo hipoplásicos y con un emplazamiento distal bilateral, con un índice de implantación de 0,19 frente a una media normal de 0,50 para su edad gestacional al nacer. Es remitido a la consulta de Genética para descartar microdeleción 22q11.2. Resultados El cariotipo y la hibridación in situ de fluorescencia (FISH) con sonda D22S75 resultaron normales y debido a los hallazgos clínicos se realizó un estudio molecular para el síndrome de Holt-Oram. Se encontró una mutación en el intrón 7 de TBX5 que produce una probable alteración del splicing del gen que da lugar a una proteína truncada en su extremo C-terminal. Los padres del propósito presentan una secuencia normal para el gen, lo que indica que la mutación se produjo de novo, sin que pueda descartarse un mosaicismo germinal en los padres. Conclusiones El síndrome de Holt-Oram es la causa más frecuente de síndrome cardiomiélico. Debería ser objeto de estudio molecular todo niño con malformaciones cardíacas y alteraciones de las extremidades superiores como pulgares ausentes, hipoplásicos, distalmente emplazados o trifalángicos

Introduction Cardiomyelic syndromes encompass congenital heart disease and skeletal malformations of the upper limbs and are related to mutations in transcription factors with T-Box domains. Holt-Oram syndrome is caused by a dominant mutation in the TBX5 gene that alters the three-dimensional structure of the protein and its DNA binding function. Several point mutations and deletions in TBX5 have been reported in patients with the Holt-Oram syndrome phenotype. Patients and methods The proband was a boy with a large atrial septal defect ostium secundum type and a ventricular septal defect, diagnosed by clinical findings (heart murmur) and echocardiography. He also presented slightly hypoplastic thumbs with distal bilateral placement and an implantation index of 0.19 (compared with an average of 0.50 for his gestational age at birth). The boy was referred to the department of medical genetics to rule out 22q11.2 microdeletion syndrome. Results Karyotype and fluorescence in situ hybridization at locus D22S75 were both normal. Because of his clinical findings, molecular study for Holt-Oram syndrome was indicated, leading to the finding of a mutation at intron 7 of TBX5, probably producing a splicing alteration of the gene and resulting in a protein truncated at its C-terminal end. The proband's parents presented the wild type sequence of the gene, thus indicating that the mutation was produced de novo, although a possible germinal mosaicism in the parents could not be ruled out. Conclusions Holt-Oram syndrome is the most frequent cause of cardiomyelic syndrome. All children with heart malformations and abnormalities of the upper limbs such as absent, hypoplastic, distally placed or triphalangic thumbs should undergo molecular studies for this syndrome

Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample.

Association between attention-deficit hyperactivity disorder (ADHD) and the 10-repeat allele of the dopamine transporter gene (DAT1) has been reported in independent clinical samples using a categorical clinical definition of ADHD. The present study adopts a quantitative trait loci (QTL) approach to examine the association between DAT1 and a continuous measure of ADHD behaviours in a general-population sample, as well as to explore whether there is an independent association between DAT1 and performance on neuropsychological tests of attention, response inhibition, and working memory. From an epidemiological sample of 872 boys aged 6-11 years, we recruited 58 boys scoring above the 90th percentile for teacher reported ADHD symptoms (SWAN ADHD scale) and 68 boys scoring below 10th percentile for genotyping and neuropsychological testing. A significant association was found between the DAT1 homozygous 10/10-repeat genotype and high-scoring boys (chi(2)square=4.6, P<0.03; odds ratio=2.4, 95% CI 1.1-5.0). Using hierarchical linear regression, a significant independent association was found between the DAT1 10/10-repeat genotype and measures of selective attention and response inhibition after adjusting for age, IQ, and ADHD symptoms. There was no association between DAT1 and any component of working memory. Furthermore, performance on tasks of selective attention although associated with DAT1 was not associated with SWAN ADHD high scores after controlling for age and IQ. In contrast, impairment on tasks that tapped sustained attention and the central executive component of working memory were found in high-scoring boys after adjusting for age and IQ. The results suggest that DAT1 is a QTL for continuously distributed ADHD behaviours in the general population and the cognitive endophenotype of response inhibition.

Plantar fasciopathy and orthotripsy: the effect of prior cortisone injection.

BACKGROUND: Corticoid steroid injection into the heel is a popular treatment method for painful heel syndromes. However, the positive results usually are short term. Extracorporeal shock wave treatment (ESW) has been shown to have a more permanent effect. We evaluated 555 patients who received ESW using the device Ossa Tron Orthotripsy (Health Tronics, Surgical Services, Marietta, GA) relative to antecedent cortisone heel injection. METHODS: Before ESW, 312 patients (56%) received one or more cortisone injections into the heel, and 243 patients (44%) had never received a cortisone injection. RESULTS: Two hundred and thirty-four patients (75%) who had antecedent injection or injections had positive outcomes after ESW. One hundred sixty-eight patients (69%) without prior heel injection had positive responses after ESW. CONCLUSION: The prior injection of cortisone did not affect the likelihood of a positive response to ESW. Similarly, the absence of prior injection of cortisone did not affect the outcome.

Influence of corn variety and cutting height on nutritive value of silage fed to lactating dairy cows.

Two corn varieties predicted to differ in digestibility were harvested at 2 cutting heights (10.2 or 30.5 cm) to determine effects on the nutrient content of the resulting silage, nutrient intake, nutrient digestibility, and production of lactating cows fed such corn silage originally harvested at two-thirds milk line. Acid detergent fiber (ADF) concentration was higher and in vitro true dry matter (DM) digestibility (IVTDMD) was lower for the variety predicted to have average digestibility. An interaction was observed between variety and cutting height because of decreased ADF and increased IVTDMD for the average digestibility variety cut at 30.5 vs. 10.2 cm; no differences were observed for the higher digestibility variety at each cutting height. When silages were fed to 32 Holstein cows in a 5-wk randomized design trial, DM intake, milk yield, and milk composition were similar. There was an interaction between variety and cutting height for DM intake and total tract apparent digestibility of DM, crude protein, and neutral detergent fiber because of lower intake and digestibility for the diets containing either the high cut, average quality variety or low cut, higher quality variety. These results suggest that increasing the cutting height to 30.5 cm does not improve silage quality or improve milk yield of cows. Although the 2 varieties selected for this trial were predicted to differ in digestibility, these differences were not great enough to influence milk yield or composition of lactating cows.

Bilateral chronic proximal plantar fasciopathy: treatment with electrohydraulic orthotripsy.

BACKGROUND: Patients presenting for treatment of chronic plantar fasciopathy often have bilateral involvement. When various nonoperative treatments fail, subsequent intervention may be problematic, especially since bilateral surgery (bilateral fascial release) may not be realistic because of variable, frequently restrictive postoperative weightbearing limitations. METHODS: Twenty-three patients (46 heels) were treated with electrohydraulic high-energy orthotripsy to the plantar entheses of both feet while under the same anesthesia (conscious sedation). Following orthotripsy, all patients immediately were fully weightbearing and resumed normal activities of daily living and work, usually within 24 hours. Progressive return to athletic activities was allowed. Patients were assessed by three outcome parameters: (1) pain measured objectively by a dolorimeter combined with the patient's subjective evaluation of the level of pain; (2) pain after 5 minutes of walking upon arising; and (3) pain with daily activities. All pain measurements were done by the visual analog scale. RESULTS: Patients initially experienced varied pain relief responses. This included earlier pain relief in one heel compared to the other, as well as better pain relief in one heel than the other at the 6- and 12-week evaluations, but with much less variance at the 1-year evaluation. By 3 months following orthotripsy, 28 heels (61%) had good or excellent results. These results were maintained or improved at 1 year. In 18 heels (39%), the outcome was fair or poor. Nineteen heels received a second orthotripsy application; one patient requested a second orthotripsy treatment of only one heel, while nine patients requested a second treatment of both heels. The outcome showed further improvement following the second application of orthotripsy. At 1 year after one or two orthotripsy applications, 19 patients (38 heels) were satisfied with the results in both heels (83%), while four patients (eight heels) still had an unsatisfactory outcome (17%). CONCLUSION: Electrohydraulic high-energy orthotripsy is a reasonable nonincisional method for treating patients with bilateral chronic proximal plantar fasciopathy under a single anesthetic without the prolonged nonweightbearing status often recommended for patients following unilateral open or endoscopic fascial release.

Are medullary breast cancers an indication for BRCA1 mutation screening? A mutation analysis of 42 cases of medullary breast cancer.

Recommended guidelines have limited breast cancer gene ( BRCA1 ) mutation testing to individuals with a personal or family history of early onset breast and/or ovarian cancer, and those with multiple affected close relatives. Such large breast cancer families are rare in the general population, limiting the clinical application of the BRCA1 discovery. Previous reports have suggested an association between medullary breast cancer and BRCA1 mutation carriers. To test the feasibility of using these rare histological subtypes as an alternative to epidemiological factors, 42 cases of medullary cancer unselected for family history were screened for BRCA1 point mutations and large exon rearrangements. The large majority (83%) of these patients did not have significant family of breast or ovarian cancer. Two deleterious mutations resulting in a premature stop codon, and one exon 13 duplication were found. All mutations were detected in patients with typical medullary cancer, who had family history of multiple breast and ovarian cancers. Our findings suggest that medullary breast cancers are not an indication for BRCA1 mutation screening in the absence of significant family risk factors.