FDA Public Workshop Summary-Addressing Challenges in Inhaled Antifungal Drug Development.

Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On September 25, 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights.

[Clinical efficacy of combined therapy in children with stage 4 neuroblastoma]. / 儿童4期神经母细胞瘤联合治疗的临床疗效观察.

OBJECTIVES: To study the early clinical efficacy of combined therapy of stage 4 neuroblastoma. METHODS: A retrospective analysis was performed on the medical data and follow-up data of 14 children with stage 4 neuroblastoma who were diagnosed in Hong Kong University-Shenzhen Hospital from January 2016 to June 2021. RESULTS: The median age of onset was 3 years and 7.5 months in these 14 children. Among these children, 9 had positive results of bone marrow biopsy, 4 had N-Myc gene amplification, 13 had an increase in neuron-specific enolase, and 7 had an increase in vanilmandelic acid in urine. Based on the results of pathological examination, differentiated type was observed in 6 children, undifferentiated type in one child, mixed type, in one child and poorly differentiated type in 6 children. Of all the children, 10 received chemotherapy with the N7 regimen (including 2 children receiving arsenic trioxide in addition) and 4 received chemotherapy with the Rapid COJEC regimen. Thirteen children underwent surgery, 14 received hematopoietic stem cell transplantation, and 10 received radiotherapy. A total of 8 children received Ch14.18/CHO immunotherapy, among whom 1 child discontinued due to anaphylactic shock during immunotherapy, and the other 7 children completed Ch14.18/CHO treatment without serious adverse events, among whom 1 child was treated with Lu177 Dotatate 3 times after recurrence and is still undergoing chemotherapy at present. The median follow-up time was 45 months for all the 14 children. Four children experienced recurrence within 2 years, and the 2-year overall survival rate was 100%; 4 children experienced recurrence within 3 years, and 7 achieved disease-free survival within 3 years. CONCLUSIONS: Multidisciplinary combined therapy is recommended for children with stage 4 neuroblastoma and can help them achieve better survival and prognosis.

Survival prediction in patients with chronic obstructive pulmonary disease following a pulmonary rehabilitation programme in Hong Kong.

BACKGROUND AND OBJECTIVE: Pulmonary rehabilitation programme (PRP) is an important component in the management of chronic obstructive pulmonary disease (COPD). However, to date so far there has been limited literature on the survival outcomes of patients with COPD after a PRP in Hong Kong. This study aimed to investigate the outcomes of a pulmonary rehabilitation programme on the survival rates of a retrospective cohort of patients with COPD. METHODS: This was a retrospective study that included subjects who participated in the PRP in a rehabilitation hospital from the year 2003 to 2015. A total of 431 patients with chronic obstructive pulmonary disease were identified from the electronic record system of the hospital. The dataset were split into two age groups for reporting and analysis using the mean age of 72 as the cut-off. Their median survival times were calculated using Kaplan-Meier analysis. Cox-proportional regression model was used to explore factors that predicted better survival. The most significant predictors were used as strata, and their respective effects on survival functions were analysed with Kaplan-Meier analysis again. RESULTS: The overall median survival of the cohort was 4.3 years. The median survival times of the younger patient group (aged <72) and the older patient group (aged ≥72) were 5.3 and 3.6 years, respectively. For the patients, aged <72 years old, Moser's Activities of Daily Living class and the pulmonary rehabilitation programme completion rate were the most significant survival predictors. For the patients aged ≥72 years old, Monitored Functional Task Evaluation score was the most significant survival predictor. CONCLUSION: Moser's Activities of Daily Living class ≥2 and non-completion of PRP for younger group, low exercise capacity with Monitored Functional Task Evaluation score <17 for older group were identified as significant predictors of poor survival. The findings of this study helped identifying those patients with COPD who have the needs to be more intensively treated and closely monitored.

Use of Proprietary Names by Prescribers for Generic Products.

BACKGROUND: Proprietary names are often used when prescribing drug products in the United States. The purpose of this study is to describe prescribers' use of proprietary names for generic products, branded-generic names, on prescription orders and to identify prescribing practice trends to inform the development and evaluation of new proprietary names. METHODS: To identify Abbreviated New Drug Application (ANDA) with branded-generic names approved between January 2003 and December 2012, we utilized the database provided by the FDA Office of Communications, Drugs@FDA . A national outpatient retail prescription database, IMS's Vector One: National (VONA) was used to identify prescribing trends by examining data for branded-generic names identified in Drugs@FDA as they were written on prescriptions for years 2003 to 2012, the last year of data collection for VONA. IMS Health, IMS National Sales Perspectives (IMS NSP) was used to retrieve the date that product sales were first reported (launch date). RESULTS: Our search of Drugs@FDA identified 65 distinct branded-generic names approved between January 2003 and December 2012. Data show that most of these products with branded-generic names are written on prescriptions and sold to pharmacies within a year of FDA approval. In some cases, the use of branded-generic names persists for up to 9 years after drug approval. CONCLUSION: This descriptive study confirmed that branded-generic names are used in prescribing. Thus, evaluation of orthographic and phonetic similarities between proposed proprietary names and branded-generic names is necessary when formulating and evaluating new proprietary names.

Singapore Paediatric Resuscitation Guidelines 2016.

We present the revised 2016 Singapore paediatric resuscitation guidelines. The International Liaison Committee on Resuscitation's Pediatric Taskforce Consensus Statements on Science and Treatment Recommendations, as well as the updated resuscitation guidelines from the American Heart Association and European Resuscitation Council released in October 2015, were debated and discussed by the workgroup. The final recommendations for the Singapore Paediatric Resuscitation Guidelines 2016 were derived after carefully reviewing the current available evidence in the literature and balancing it with local clinical practice.

Characteristics That May Help in the Identification of Potentially Confusing Proprietary Drug Names.

PURPOSE: This study aimed to provide a descriptive analysis of characteristics that are common among drug name pairs involved in name confusion medication errors. METHODS: We evaluated drug name pairs that contained at least one proprietary name from the Institute for Safe Medication Practices (ISMP) List of Confused Drug Names. For each name pair, we analyzed whether the following characteristics were present: (1) the same first letter, (2) a shared letter string of at least 3 letters, and (3) similarity in the number of letters. Additionally, we obtained the combined Phonetic and Orthographic Computer Analysis (POCA) score. RESULTS: Ninety-nine percent of the drug name pairs reflected at least one of the 3 characteristics analyzed. Additionally, 75% of the names had a combined POCA score of ≥50%. CONCLUSIONS: This descriptive analysis provides some insight into characteristics that may be associated with name confusion, which should be considered when formulating and evaluating proposed proprietary drug names.

Effects of Arm Weight Support Training to Promote Recovery of Upper Limb Function for Subacute Patients after Stroke with Different Levels of Arm Impairments.

Purpose. The goal of this study was to investigate the effects of arm weight support training using the ArmeoSpring for subacute patients after stroke with different levels of hemiplegic arm impairments. Methods. 48 inpatients with subacute stroke, stratified into 3 groups from mild to severe upper extremity impairment, were engaged in ArmeoSpring training for 45 minutes daily, 5 days per week for 3 weeks, in addition to conventional rehabilitation. Evaluations were conducted at three measurement occasions: immediately before training (T1); immediately after training (T2); and at a 3-week follow-up (T3) by a blind rater. Results. Shoulder flexion active range of motion, Upper Extremity Scores in the Fugl-Meyer Assessment (FMA), and Vertical Catch had the greatest differences in gain scores for patients between severe and moderate impairments, whereas FMA Hand Scores had significant differences in gain scores between moderate and mild impairments. There was no significant change in muscle tone or hand-path ratios between T1, T2, and T3 within the groups. Conclusion. Arm weight support training is beneficial for subacute stroke patients with moderate to severe arm impairments, especially to improve vertical control such as shoulder flexion, and there were no adverse effects in muscle tone.

Adrenal Cushing's syndrome in pregnancy: Clinical and molecular characterisation of a case.

BACKGROUND: Cushing's syndrome is rare during pregnancy and more commonly due to adrenal pathology, in contrast to the non-pregnant population. Increased levels of cortisol-binding globulin and placental production of corticotropin-releasing hormone and adrenocorticotropic hormone complicate the diagnostic strategies usually employed. CASE: A 32-year-old G1P0 at 15/40 gestation presented with severe peripheral oedema and excessive weight gain. Examination revealed pitting oedema to the abdominal wall, wide violaceous striae, moon facies and acne. Cortisol excess was confirmed with elevated 24 h urinary free cortisol, raised midnight salivary cortisol and lack of diurnal variation. Adrenocorticotropic hormone ranged between 22 and 36 pg/ml (5-8 pmol/L). Fetal ultrasound confirmed a single live intrauterine gestation with an incidental finding of a maternal left adrenal mass. Magnetic resonance imaging confirmed an adrenal mass measuring 3.0 × 4.4 × 4.1 cm. She underwent a laparoscopic left adrenalectomy at 18 weeks' gestation without complication. Her postoperative cortisol level was undetectable. Hydrocortisone replacement was commenced with slow weaning as an outpatient. Histology was consistent with an adrenal adenoma. Immunohistochemistry revealed strong staining for the luteinising hormone/choriogonadotropin receptor, and expression of the luteinising hormone/choriogonadotropin receptor gene was in the range seen in normal ovary. DNA analysis revealed a mutation in GNAS encoding the Gα subunit in the cyclic adenosine monophosphate pathway. CONCLUSION: Cushing's syndrome may present in pregnancy as a result of ßhCG acting on the luteinising hormone/choriogonadotropin receptor over-expression by the adenoma amplifying the aberrant cyclic adenosine monophosphate signaling implicated in the development of cortisol-secreting adenomas.

Assessment and management of male androgen disorders: an update.

BACKGROUND: Male hypogonadism, caused by intrinsic pathology of the hypothalamic-pituitary-testicular (HPT) axis, is an under-diagnosed condition not to be missed. By contrast, late onset hypogonadism (LOH), due to functional suppression of the HPT axis from age-related comorbidities, may be less common than previously believed. OBJECTIVE: This article outlines the aetiology, clinical features, investigation and management of male hypogonadism and discusses the more controversial area of LOH. DISCUSSION: Pathologically based hypogonadism is, after a thorough diagnostic work-up, treated with testosterone replacement therapy, unless fertility is desired. LOH with modest reductions in testosterone levels should primarily be managed by attention to lifestyle measures, especially weight loss, and optimisation of comorbidities. Clear treatment goals should be identified, and efficacy and safety should be monitored according to published clinical practice guidelines.

Issues about home computer workstations and primary school children in Hong Kong: a pilot study.

BACKGROUND: All around the world, there is a rising trend of computer use among young children especially at home; yet the computer furniture is usually not designed specifically for children's use. In Hong Kong, this creates an even greater problem as most people live in very small apartments in high-rise buildings. Most of the past research literature is focused on computer use in children in the school environment and not about the home setting. OBJECTIVE: The present pilot study aimed to examine ergonomic issues in children's use of computers at home in Hong Kong, which has some unique home environmental issues. PARTICIPANTS: Fifteen children (six male, nine female) aged 8-11 years and their parents were recruited by convenience sampling. METHODS: Participants were asked to provide information on their computer use habits and related musculoskeletal symptoms. Participants were photographed when sitting at the computer workstation in their usual postures and joint angles were measured. RESULTS: The participants used computers frequently for less than two hours daily and the majority shared their workstations with other family members. Computer furniture was designed more for adult use and a mismatch of furniture and body size was found. Ergonomic issues included inappropriate positioning of the display screen, keyboard, and mouse, as well as lack of forearm support and suitable backrest. These led to awkward or constrained postures while some postural problems may be habitual. Three participants reported neck and shoulder discomfort in the past 12 months and 4 reported computer-related discomfort. CONCLUSIONS: Inappropriate computer workstation settings may have adverse effects on children's postures. More research on workstation setup at home, where children may use their computers the most, is needed.

Emergency use authorization for intravenous peramivir: evaluation of safety in the treatment of hospitalized patients infected with 2009 H1N1 influenza A virus.

BACKGROUND: On 23 October 2009, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for intravenous peramivir, an unapproved antiviral, to treat suspected or confirmed 2009 H1N1 influenza A virus infection. Eligible hospitalized patients were unresponsive to or unable to tolerate available antivirals or lacked dependable oral or inhaled drug delivery routes. The EUA required healthcare providers to report medication errors, selected adverse events (AEs), serious AEs, and deaths to the FDA. METHODS: An FDA safety team analyzed reports submitted to the Adverse Event Reporting System (AERS) and sought follow-up in selected cases. RESULTS: The FDA received AERS reports for 344 patients (including 28 children and 3 pregnant women). Many patients were critically ill on mechanical ventilation (41%) and renal replacement therapies (19%); 38% had received oseltamivir. The most frequently reported serious AEs by MedDRA preferred term were death (15%), H1N1 influenza (8%), respiratory failure (8%), acute renal failure (7%), and acute respiratory distress syndrome (7%). Six medication errors were reported. Most deaths occurred among patients who were obese, immunosuppressed, aged >65 years, or received oseltamivir. Rash was the only treatment-emergent AE attributable to peramivir. Influenza severity, comorbidities, and concomitant medications confounded additional peramivir AE assessments. Missing clinical and laboratory data precluded evaluation of some reports. CONCLUSIONS: Many peramivir recipients under the EUA were critically ill and at risk for influenza-related complications. The safety data were insufficient to assess whether peramivir affected outcome or caused adverse reactions other than rash. Clinical trials in hospitalized patients with serious influenza infections should provide additional information.

Low testosterone levels as an independent predictor of mortality in men with chronic liver disease.

OBJECTIVE: To examine the prevalence and prognostic implications of low serum testosterone levels in men with chronic liver disease. DESIGN: We conducted an observational study at a tertiary referral centre. PATIENTS AND MEASUREMENTS: Baseline serum testosterone was measured in 171 men presenting to the Victorian Liver Transplant Unit for liver transplant evaluation. Patients were followed up to liver transplant or death. RESULTS: Sixty-one per cent of men had a low total testosterone level (TT, <10 nm), and 90% of men had a low calculated free testosterone level (cFT, <230 pm). During the available observation time (median 8 months, interquartile range 4-14 months), 56 men (33%) died and 63 (37%) received a liver transplant. Fifty-two (30%) survived without a transplant. Median time to death was 8 months (range 2-13) and to liver transplant was 8 months (4-14). Baseline low TT and cFT levels both (P < 0·0001) predicted mortality. Moreover, in a Cox proportional hazard model, both low total (P = 0·02) and free testosterone (P = 0·007) levels remained predictive of death independently of established prognostic factors, such as the model for end-stage liver disease (MELD) score and serum sodium levels. A decrease in TT by 1 nm and in cFT by 10 pm was associated with an 8% increase in mortality. CONCLUSIONS: Low testosterone levels are common in men with severe liver disease and predict mortality independent of MELD, the standard score used to prioritize the allocation of liver transplants.

Noninvasive ventilation in children: a review.

OBJECTIVE: To assess the use of noninvasive ventilation (NIV) in children and its application in the acute and chronic setting of pediatric respiratory failure. SOURCES: Search of pertinent articles within PubMed, Cochrane and Ovid MEDLINE databases from 1950 to 2007, using the keywords pediatrics, noninvasive ventilation and positive airway pressure. SUMMARY OF THE FINDINGS: There is a paucity of published data on pediatric NIV. The majority of the data available are case reports or small case series, with a number of small, randomized studies reported. CONCLUSION: Although the use of NIV is increasingly recognized in pediatrics, there are currently still no generally accepted guidelines for its use. In the chronic setting, its use has mainly been proven in obstructive sleep apnea and respiratory failure secondary to neuromuscular disorders. It would appear that the major challenge is ensuring compliance, and this can be enforced by patient/caregiver education, use of a suitable interface, heated humidifiers and by minimizing the side effects of NIV. In the setting of acute respiratory failure, it would appear from available data that success is usually predicted by the rapidity of response. Patients placed on NIV should be monitored closely and this mode of ventilation should be reviewed if there is a lack of response within a few hours after commencement of therapy.

Ventilação não-invasiva em crianças: uma revisão / Noninvasive ventilation in children: a review

OBJETIVO: Avaliar o uso de ventilação não-invasiva (VNI) em crianças e sua aplicação na insuficiência respiratória aguda e crônica. FONTES DOS DADOS: Busca de artigos pertinentes no Pubmed, base de dados Cochrane e Ovid MEDLINE entre 1950 e 2007, através do emprego dos termos pediatria, ventilação não-invasiva e pressão positiva nas vias aéreas. SíNTESE DOS DADOS: Há uma escassez de publicações acerca da VNI em pediatria. A maioria dos dados disponíveis diz respeito a relatos de caso ou pequenas séries de casos, com apenas alguns estudos randomizados pequenos. CONCLUSÃO: Embora o uso de VNI seja cada vez mais reconhecido em pediatria, atualmente não existem ainda orientações gerais para o seu uso. Nos casos crônicos, seu uso foi eficaz no tratamento de apnéia obstrutiva do sono e na insuficiência respiratória secundária a afecções neuromusculares. Parece que o maior desafio é garantir a adesão ao tratamento e isso pode ser obtido através da instrução do paciente/cuidador, utilização de uma interface adequada, umidificadores aquecidos e minimização dos efeitos colaterais da VNI. Nos casos de insuficiência respiratória aguda, os dados disponíveis parecem indicar que se pode inferir o sucesso do tratamento pela rapidez na resposta terapêutica. Os pacientes submetidos à VNI devem ser monitorados cuidadosamente e essa modalidade de ventilação deve ser reconsiderada caso não haja resposta após algumas horas do início do tratamento.

OBJECTIVE: To assess the use of noninvasive ventilation (NIV) in children and its application in the acute and chronic setting of pediatric respiratory failure. SOURCES: Search of pertinent articles within Pubmed, Cochrane and Ovid MEDLINE databases from 1950 to 2007, using the keywords "pediatrics", "noninvasive ventilation" and "positive airway pressure". SUMMARY OF THE FINDINGS: There is a paucity of published data on pediatric NIV. The majority of the data available are case reports or small case series, with a number of small, randomized studies reported. CONCLUSION: Although the use of NIV is increasingly recognized in pediatrics, there are currently still no generally accepted guidelines for its use. In the chronic setting, its use has mainly been proven in obstructive sleep apnea and respiratory failure secondary to neuromuscular disorders. It would appear that the major challenge is ensuring compliance, and this can be enforced by patient/caregiver education, use of a suitable interface, heated humidifiers and by minimizing the side effects of NIV. In the setting of acute respiratory failure, it would appear from available data that success is usually predicted by the rapidity of response. Patients placed on NIV should be monitored closely and this mode of ventilation should be reviewed if there is a lack of response within a few hours after commencement of therapy.

A study of the reliability and validity of the Chinese version of the Dementia Rating Scale.

BACKGROUND: The present study aims to develop and validate a Chinese version of the Dementia Rating Scale (DRS) for use with Chinese populations in psychogeriatric settings. METHODS: The DRS was translated into Chinese and its content validity was evaluated by an 11-member expert panel. To assess reliability and concurrent validity, 52 subjects with dementia were recruited from medical and psychogeriatric settings using purposive sampling. RESULTS: With percentage of agreement as an indicator, 28 out of 36 items (78%) had satisfactory content validity. Items with a percentage of agreement below 70% were reviewed and modified, based on the comments of the experts. The CDRS had excellent test-retest and inter-rater reliability, with intraclass correlation coefficient (ICC) at 0.94 and 0.93 respectively. Intraclass correlation coefficients ranged between 0.75 and 0.89 for the subscales. The internal consistency of the CDRS subscale, as measured by Cronbach's a, ranged from 0.57 to 0.82. The CDRS had high correlations with the Chinese Mini-mental State Examination (r = 0.80 for total score, r = 0.58 to 0.84 for subscales. CONCLUSIONS: The CDRS is a valid instrument for the assessment of dementia in Chinese-speaking subjects.

Severe acute respiratory syndrome (SARS) in a paediatric cluster in Singapore.

BACKGROUND: Severe acute respiratory syndrome (SARS) is a major infectious disease pandemic that occurred in early 2003, and one of the diagnostic criteria is the presence of chest radiographic findings. OBJECTIVE: To describe the radiographic features of SARS in a cluster of affected children. MATERIALS AND METHODS: The chest radiographs of four related children ranging in age from 18 months to 9 years diagnosed as having SARS were reviewed for the presence of air-space shadowing, air bronchograms, peribronchial thickening, interstitial disease, pleural effusion, pneumothorax, hilar lymphadenopathy and mediastinal widening. RESULTS: Ill-defined air-space shadowing was the common finding in all the children. The distribution was unifocal or multifocal. No other findings were seen on the radiographs. None of the children developed radiographic findings consistent with acute respiratory distress syndrome. All four children showed significant resolution of the radiographic findings 4-6 days after the initial radiograph. CONCLUSIONS: Early recognition of these features is important in implementing isolation and containment measures to prevent the spread of infection. SARS in children appears to manifest as a milder form of the disease as compared to adults.

Translation challenges of cross-cultural research and program development.

PURPOSE: Translation of cross-cultural surveys and programs pose unique challenges. This paper identifies potential pitfalls of current translation guidelines and presents solutions employed for one project. METHODS: We followed current guidelines for translation of survey instruments including forward and back translation, and also utilized qualitative methods to decenter survey questions. In addition, our project adapted translation by committee with a core translation team of bilingual/trilingual investigators and staff members with diverse skills and complementary degrees of proficiency in the languages and dialects of interest. PRINCIPAL FINDINGS: This approach resulted with a mechanism for emic equivalence, identifying and resolving dialectic and sociolinguistic concerns, selecting appropriate written Chinese styles, and providing appropriate linguistic training to interviewers. CONCLUSIONS: An understanding of the history of a people and its ramifications for the language are important components of the translation process. Allocation of appropriate time, resources, and skills are critical to the successful development of valid cross-cultural survey instruments and effective programs.