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Michael Williams

Publications and source records attributed to Michael Williams.

At least 19 recordsLinked to original sources
PubMed2025

Absolute quantification of the living skin microbiome overcomes relic-DNA bias and reveals specific patterns across volunteers.

BACKGROUND: As the first line of defense against external pathogens, the skin and its resident microbiota are responsible for protection and eubiosis. Innovations in DNA sequencing have significantly increased our knowledge of the skin microbiome. However, current characterizations do not discriminate between DNA from live cells and remnant DNA from dead organisms (relic DNA), resulting in a combined readout of all microorganisms that were and are currently present on the skin rather than the actual living population of the microbiome. Additionally, most methods lack the capability for absolute quantification of the microbial load on the skin, complicating the extrapolation of clinically relevant information. RESULTS: Here, we integrated relic-DNA depletion with shotgun metagenomics and bacterial load determination to quantify live bacterial cell abundances across different skin sites. Though we discovered up to 90% of microbial DNA from the skin to be relic DNA, we saw no significant effect of this on the relative abundances of taxa determined by shotgun sequencing. Relic-DNA depletion prior to sequencing strengthened underlying patterns between microbiomes across volunteers and reduced intraindividual similarity. We determined the absolute abundance and the fraction of population alive for several common skin taxa across body sites and found taxa-specific differential abundance of live bacteria across regions to be different from estimates generated by total DNA (live + dead) sequencing. CONCLUSIONS: Our results reveal the significant bias relic DNA has on the quantification of low biomass samples like the skin. The reduced intraindividual similarity across samples following relic-DNA depletion highlights the bias introduced by traditional (total DNA) sequencing in diversity comparisons across samples. The divergent levels of cell viability measured across different skin sites, along with the inconsistencies in taxa differential abundance determined by total vs live cell DNA sequencing, suggest an important hypothesis for certain sites being susceptible to pathogen infection. Overall, our study demonstrates a characterization of the skin microbiome that overcomes relic-DNA bias to provide a baseline for live microbiota that will further improve mechanistic studies of infection, disease progression, and the design of therapies for the skin. Video Abstract.

Humans↗
PubMed2006

Armodafinil, the R-enantiomer of modafinil: wake-promoting effects and pharmacokinetic profile in the rat.

Modafinil reduces the excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. In rats, modafinil promotes dose-dependent increases in wake duration. The wake-promoting activity of the R-enantiomer of modafinil (armodafinil) was evaluated in WKY rats and compared to the classical stimulant, D-methamphetamine. Electroencephalographic and electromyographic signals were assessed via a tethered cranial implant. Body temperature and locomotor activity were assessed by telemetry via intraperitoneal implant. Rats (n=60, 12 per group) were subjected to one of five parallel treatments: armodafinil at 30, 100 and 300 mg/kg i.p.; D-methamphetamine, 1 mg/kg i.p. and vehicle. Armodafinil and D-methamphetamine increased time spent awake relative to vehicle. Armodafinil-evoked increases in wake duration were dose-dependent and proportional to plasma compound exposure. Induction of wakefulness by D-methamphetamine was associated with an approximately two-fold increase in locomotor activity during the 2-h period immediately following administration relative to vehicle. D-methamphetamine also increased body temperature over the same time interval. The dose of armodafinil (100 mg/kg, i.p.) that was closest to D-methamphetamine in its wake-promoting efficacy did not produce changes in either body temperature or the intensity of locomotor activity relative to vehicle. Acute rebound hypersomnolence, characterized by increases in non-rapid eye movement sleep (NREMS) as a percentage of time and NREMS bout duration and by a decreased frequency of brief awakenings following sleep deprivation, occurred following D-methamphetamine-but not armodafinil-induced wake in this rat model which has been shown to be predictive of human drug responses.

Animals↗
PubMed2006

Recent clinical failures in Parkinson's disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases.

Understanding the mechanisms of neuronal death in concert with the identification of drugable molecular targets key to this process has held great promise for the development of novel chemical entities (NCEs) to halt neurodegenerative disease progression. Two key targets involved in the apoptotic process identified over the past decade include the mixed lineage kinase (MLK) family and glyceraldehyde phosphate dehydrogenase (GAPDH). Two NCEs, CEP-1347 and TCH346, directed against these respective targets have progressed to the clinic. For each, robust neuroprotective activity was demonstrated in multiple in vitro and in vivo models of neuronal cell death, but neither NCE proved effective Parkinson's disease (PD) patients. These recent clinical failures require a reassessment of both the relevance of apoptosis to neurodegenerative disease etiology and the available animal models used to prioritize NCEs for advancement to the clinic in this area.

Animals↗
PubMed2006

Can aquatic distribution of human pharmaceuticals be related to pharmacological data?

The recognition of pharmaceuticals as significant environmental contaminants has only been a recent phenomenon. Therefore there is a paucity of data relating to the fate and effects of pharmaceuticals once they enter an aquatic receiving system. The amount of work that needs to be done in terms of risk assessment for pharmaceuticals required by regulatory agencies is substantial. This paper has determined the environmental partitioning coefficient (K(d)) of 13 diverse human pharmaceuticals in three model systems of differing combinations of solid phases and solutions. The K(d) values were then compared with distribution values of the pharmaceuticals in the human body determined from pharmacological studies. This was done to assess the functional relationship between K(d) and distribution values in the human body (V(D)). K(d) values ranged from 3 to 2450 L kg(-1). Regression coefficients ranged from r(2)=0.62-0.72, indicating that V(D) values are a useful indicator for the K(d) values of the tested pharmaceuticals within the batch sorption systems. The relationship between K(d) and V(D) should therefore be further explored to determine whether this relationship can be applied to a broader range of pharmaceuticals in more diverse environmental systems. Exploiting available human pharmacological data in such a way would be of great benefit in prioritising human pharmaceuticals as environmental contaminants in the risk assessment process.

Chromatography, High Pressure Liquid↗
PubMed2006

Microdebrider tonsillotomy vs electrosurgical tonsillectomy: a randomized, double-blind, paired control study of postoperative pain.

OBJECTIVE: To examine whether microdebrider intracapsular tonsillotomy (MT) results in less postoperative pain compared with electrosurgical extracapsular tonsillectomy (ET). DESIGN: Prospective, randomized, double-blind, matched pair, clinical trial. SETTING: Specialty care hospital. Patients Twelve male (48%) and 13 female (52%) children aged 5 to 15 years, with obstructive tonsillar hyperplasia were randomized to have one tonsil removed by MT and the other by ET. INTERVENTIONS: An angled endoscopic microdebrider was used to perform MT, and ET was performed by standard monopolar cautery technique. Parents and children were blinded to the side of MT and ET. Children rated the pain 0 to 5 by side using the Faces Pain Scale-Revised. Blinded data collection was via telephone daily for 2 weeks by a study nurse. MAIN OUTCOME MEASURES: Primary: postoperative pain as recorded by Faces Pain Scale-Revised; secondary, presence or absence of otalgia and postoperative bleeding. RESULTS: Twenty-two children (88%) had tonsillectomy and adenoidectomy, while 3 children (12%) had tonsillectomy alone. On postoperative days 1 to 9, children reported significantly less pain on the MT side compared with the ET side (paired t test; P<.01). By postoperative days 10 to 14, the difference between sides disappeared. Twenty children (80%) reported otalgia, and it was always unilateral. For those children reporting otalgia, there was a 100% correlation between the side of otalgia and the side of ET. There was no posttonsillectomy bleeding among the 25 children. CONCLUSION: Microdebrider intracapsular tonsillotomy is significantly less painful compared with electrosurgical ET in children undergoing surgical intervention for obstructive tonsillar hypertrophy.

Adenoidectomy↗
PubMed2006

Ambulance diversion reduction: the Sacramento solution.

PURPOSE: The diversion of ambulances away from their intended emergency departments (EDs) in the United States has become commonplace and may compromise patient care. Although ambulance diversion resulting from ED overcrowding has been well described in the literature, little is known about how to reduce the incidence of ambulance diversion on a regional level. We describe the development, implementation, and impact of a region-wide program to reduce ambulance diversion. BASIC PROCEDURES: This study was undertaken in the greater Sacramento, California region from January 2001 to December 2003. This comprehensive ambulance diversion reduction program was implemented May 15, 2002, with analysis of data for this 3-year time frame. The data for this study were obtained from 17 hospitals with ambulance diversion hours being the main outcome measure for this study. FINDINGS: The greater Sacramento region had 23785 hours of ambulance diversion in 2001. In 2003, there were 7143 ambulance diversion hours. Comparing the 17-month period before implementation of this program with the 19-month period after implementation, the difference in the means of these two groups was -1428 hours per month (95% confidence interval, -1252 to -1597), a 74% decrease in ambulance diversion hours. Notably, this reduction occurred despite overall increases in ED census (6.5%), hospital admissions from the ED (8.8%), EMS arrivals to the ED (17.1%), inpatient hospital census (7.4%), and overall Sacramento population (5.7%). CONCLUSIONS: Our results demonstrate a sizeable reduction of ambulance diversion in a large urban region after the successful implementation of a comprehensive ambulance diversion reduction program. The description of this effort may serve as a model for other regions across the country that do not have an organized approach in place for ambulance diversion, although boarding of admitted patients will still be a major hurdle to effective reduction of ambulance diversion.

Ambulances↗
PubMed2006

Economic impact of bariatrics on a general surgery practice.

Bariatric surgery is currently a rapidly growing subsection of general surgery, with exponential expansion over the past decade. Many residency programs lacked sufficient experience in bariatrics, necessitating established surgeons to consider re-training and re-vamping of their practice to enter the field. The addition of bariatric surgery to a general surgery practice can present economic consequences, which are both positive and negative. Positive consequences include a potential new revenue source with a large population base. Negative consequences include increased employees, required paper-work and office resources, increased malpractice premiums, difficulties with appropriate reimbursement, and limitations on access to appointment time for non-bariatric cases. This paper reviews the potential economic impact of bariatric surgery on a general surgery practice and possible alternatives to manage these efficiently.

Appointments and Schedules↗
PubMed2006

User needs evaluation of workplace accommodations.

This study examined the multi-faceted issues surrounding workplace accommodation for workers with disabilities. A user needs survey of 510 disabled individuals examined the types of technology and accommodations needed to perform work and employment-related activities. Workers with disabilities used a variety of workplace accommodations to overcome difficulties with functional limitations. Some differences existed in the types of accommodations used by older and younger workers who had the same functional limitation. Workers of all ages were not likely to report mental limitations, and those who did were not likely to utilize workplace accommodations, with the exception of some memory strategies. For those with hearing loss, younger workers used sign language more frequently, while pre-retirement and retirement age workers used more hearing aids. Working age adults with vision impairments used electronic documents, Braille, and CCTVs more than pre-retirement or retirement age workers. Regardless of age, workers reporting functional limitations often received no workplace accommodations.

Adult↗
PubMed2005

Use of evidence-based management for acute coronary syndrome.

AIMS: This study compared the management of acute coronary syndrome (ACS) for patients admitted to Dunedin Coronary Care with evidence-based recommendations from the American College of Cardiology / American Heart Association in 1999 and 2002 and with management reported in international and local registries. METHODS: All patients with ACS from 2001-2002 were included. RESULTS: Guidelines stated that aspirin, beta-blockers, statins, and ACE-inhibitors/angiotensin-II-blockers are appropriate treatment for acute coronary syndrome. These medications were prescribed respectively in 98%, 80%, 70% and 55% of patients on discharge. In patients with documented dyslipidaemia, Statins was prescribed in 80% on discharge. The use of ACE inhibitors was 73% in patients with impaired left ventricular function, 79% in patients with clinical heart failure and 84% in patients with anterior ST-elevation myocardial infarction (STEMI). For patients with STEMI, 67% received coronary angiography, 50% had PCI and 7% underwent inpatient coronary artery bypass grafting. For Non-ST-elevation myocardial infarction (NSTEMI), the respective numbers were 73%, 38% and 21%. Our use of evidence-based medications was consistent with published guidelines and comparable to results of international registries (CRUSADE, EUROESPIRE II, GRACE) in 2001-2002. CONCLUSION: There is good adherence to the use of evidence-based management for acute coronary syndrome in Dunedin Coronary Care Unit.

Acute Disease↗
PubMed2005

Systems and integrative biology as alternative guises for pharmacology: prime time for an iPharm concept?

Understanding the molecular basis of human disease pathophysiology is critical to accurate disease diagnosis, defining disease progression and to identifying new drugs that more specifically address target diseases. Advances in the understanding of tissue function (including draft maps of the human genome) coupled with industrial-scale, 'enabling' technologies like high throughput screening, combinatorial chemistry, proteomics, etc., have generated data on a scale never before possible. Despite this, there continues to be a dearth of new drug approvals ascribed to: (i) the challenges of working with novel, often non-validated disease targets; (ii) targeting diseases (stroke, Alzheimer's) with limited (if any) treatment and ill-defined clinical trial endpoints; (iii) enhanced regulatory hurdles for drug approval; (iv) insufficient time for the new knowledge and enabling technologies to have reached a productive level. An alternate viewpoint is that unfettered access to such technologies, where exclusion rather than integration has been the hallmark, has markedly reduced the intellectual competent of the biomedical research endeavor, with perceived technological 'quick fixes' displacing the integrative, hierarchical approach of pharmacology, that with medicinal chemistry, represents the core of the drug discovery process. After two decades of profound neglect, pharmacology has re-emerged as the key discipline in providing context to the drug discovery process, facilitating more timely, context-relevant and data-driven outcomes in the search for new drugs. Rather than viewing the future of drug discovery in terms of the 'new' biologies, systems and integrative, a rubric along the lines of iPharm, integrating both established and new technologies, is required.

Animals↗
PubMed2005

Target identification and validation in drug discovery: the role of proteomics.

Proteomics, the study of cellular protein expression, is an evolving technology platform that has the potential to identify novel proteins involved in key biological processes in the cell that may serve as potential drug targets. While proteomics has considerable theoretical promise, individual cells/tissues have the potential to generate many millions of proteins while the current analytical technologies that involve the use of time-consuming two dimensional gel electrophoresis (2DIGE) and various mass spectrometry (MS) techniques are unable to handle complex biological samples without multiple high-resolution purification steps to reduce their complexity. This can significantly limit the speed of data generation and replication and requires the use of bioinformatic algorithms to reconstitute the parent proteome, a process that does not always result in a reproducible outcome. In addition, membrane bound proteins, e.g., receptors and ion channels, that are the targets of many existing drugs, are not amenable to study due, in part, to limitations in current proteomic techniques and also to these being present in low abundance and thus disproportionally represented in proteome profiles. Subproteomes with reduced complexity have been used to generate data related to specific, hypothesis-driven questions regarding target identification, protein-interaction networks and signaling pathways. However progress to date, with the exception of diagnostic proteomics in the field of cancer, has been exceedingly slow with an inability to put such studies in the context of a larger proteome, limiting the value of the information. Additionally the pathway for target validation (which can be more accurately described at the preclinical level as target confidence building) remains unclear. It is important that the ability to measure and interrogate proteomes matches expectations, avoiding a repetition of the disappointment and subsequent skepticism that accompanied what proved to be unrealistic expectations for the rapid contribution of data based on the genome maps, to biomedical research.

Computational Biology↗
PubMed2005

Salmeterol HFA is as effective as salmeterol CFC in children and adults with persistent asthma.

In accordance with the Montreal Protocol 1987, initiatives to phase out and replace ozone-depleting chlorofluorocarbon (CFC) propellants with non-ozone-depleting propellants in metered-dose inhalers (MDIs) in the treatment of asthma and chronic obstructive pulmonary disease are underway. In view of this, two multi-centre, randomised, parallel-group, double-blind studies were conducted to compare the safety and efficacy of salmeterol xinafoate delivered by an MDI using the hydrofluoroalkane (HFA) 134a propellant with the licensed CFC formulation (Serevent) in asthmatic populations of children (4-11 years) and adults (12 years). Patients on a stable dose of inhaled corticosteroids with a scope for improvement based on mean morning peak expiratory flow (PEF) and symptoms were randomised to receive salmeterol HFA MDI 50 microg twice daily or salmeterol CFC MDI 50 microg twice daily for 12 weeks. The primary efficacy variable was mean morning PEF and secondary variables included other lung function parameters, symptom scores, use of relief medication and safety assessments. The difference between the treatments in adjusted mean morning PEF (salmeterol HFA-salmeterol CFC) were 2.5 and -3.2 L/min for per-protocol populations of children and adults, respectively. The lower limit of 95% confidence intervals for both populations was within the pre-defined limit (-15 L/min) set for non-inferiority. Similar results were observed in intent-to-treat (ITT) populations. In children, the two formulations resulted in a lack of any statistically significant difference in secondary efficacy parameters. A significant difference at endpoint in clinic forced expiratory volume in 1s was reported in favour of the HFA formulation in the adult population, although the magnitude of this effect was not considered clinically significant. The incidences of adverse events (AEs) were similar for both formulations and populations, and no safety concerns were generated. Together these data demonstrate salmeterol HFA MDI to be as effective as salmeterol CFC MDI in adults and children.

Adolescent↗
PubMed2005

Abdominal insufflation decreases blood loss and mortality after porcine liver injury.

BACKGROUND: Uncontrolled intra-abdominal bleeding is a common cause of death in trauma patients in the prehospital and perioperative settings. The detrimental effects of abdominal hypertension are well studied, but the potential therapeutic use of abdominal insufflation for hemostasis has not been fully explored. We measured the effect of abdominal insufflation on blood loss and physiologic outcomes in a swine model of blunt liver injury. METHODS: Twenty-one anticoagulated swine (32 +/- 3 kg) were anesthesized; laparotomy was performed to localize liver anatomy and to place loose tourniquettes isolating the porta hepatis and supra/infrahepatic vena cava. A captive bolt gun was used to create a grade V hepatic laceration, producing massive parenchymal injury as well as complex tears of the middle and right hepatic veins. Animals were randomized into either control (n = 10) or abdominal insufflation at 20 cm H(2)O pressure (n = 11) groups. Crystalloid was used to maintain a mean arterial pressure of 30 mm Hg. Arterial pressure and other physiologic variables were recorded for 20 minutes. Animals were then sacrificed and blood loss measured. RESULTS: Blood loss was 69% lower in insufflated animals compared with controls (384 +/- 51 versus 1252 +/- 88 cc, p < 0.001). After 20 minutes, insufflated animals had significantly higher mean arterial blood pressure (32.2 +/- 4.2 versus 21.2 +/- 4.0 mm Hg) and lower total resuscitation volume (195 +/- 83 versus 1356 +/- 95 cc). Three pigs died in the control group (30%), whereas no insufflated animals died (p < 0.05). CONCLUSION: In a swine model of catastrophic blunt hepatic injury, abdominal insufflation significantly decreased blood loss and mortality.

Abdomen↗
PubMed2005

Population-based study of medical comorbidity in early dementia and "cognitive impairment, no dementia (CIND)": association with functional and cognitive impairment: The Cache County Study.

OBJECTIVE: Authors investigated medical comorbidity in persons with dementia and "Cognitive Impairment, No Dementia" (CIND). METHODS: The Cache County Study is an ongoing population-based study of the epidemiology of dementia, the risk factors for conversion from CIND to dementia, and the progression of dementia. As part of the study's first incidence wave, persons with dementia (N=149), CIND (N=225), or without cognitive impairment (N=321) were identified and studied. Participants received comprehensive clinical evaluations and were rated on the General Medical Health Rating (GMHR), a global measure of seriousness of medical comorbidity. Participants and informants also completed the Mini-Mental State Exam and provided self-report information about comorbid medical conditions and functioning in activities of daily living. RESULTS: There were few differences in number or type of comorbid medical conditions between persons with CIND and dementia, but persons with dementia were prescribed more medications. Stroke was more common in dementia participants, but other illnesses common in old age were not significantly different across cognitive groups. Medical comorbidity was more serious in both dementia and CIND, such that both groups were less likely to have "little to no" comorbidity. Seriousness of medical comorbidity was significantly associated with worse day-to-day functioning and cognition. CONCLUSIONS: Persons with CIND and dementia have more serious medical comorbidity than comparable persons without cognitive impairment. This comorbidity may play a role in the progression of CIND and dementia. Future studies should investigate the role of medical comorbidity and its treatment on dementia onset or progression, as well as the mechanisms mediating its neuropathologic effects.

Activities of Daily Living↗
PubMed2005

Multiple laparotomies are a predictor of fascial dehiscence in the setting of severe trauma.

The purpose of this study was to determine the incidence of wound dehiscence after repeat trauma laparotomy. We performed a retrospective analysis of adult trauma patients who underwent laparotomy at an urban level 1 trauma center during the past 5 years. Patients were divided into single (SL) and multiple laparotomy (ML) groups. Demographic, clinical, and outcome data were collected. Data were analyzed using chi2, t testing, and ANOVA. Overall dehiscence rate was 0.7 per cent. Multiple laparotomy patients had damage control, staged management of their injuries, or abdominal compartment syndrome as the reason for reexploration. SL and ML patients had similar age and sex. ML patients had a higher rate of intra-abdominal abscess than SL patients (13.7% vs 1.2% P < 0.0001), but intra-abdominal abscess did not predict wound dehiscence in the ML group (P = 0.24). This was true in spite of the fact that ML patients had a significantly higher Injury Severity Score (ISS) than SL patients (21.68 vs 14.35, P < 0.0001). Interestingly, wound infection did not predict dehiscence. Patients undergoing repeat laparotomy after trauma are at increased risk for wound dehiscence. This risk appears to be associated with intraabdominal abscess and ISS, but not wound infection. Surgeons should leave the skin open in the setting of repeat trauma laparotomy, which will allow serial assessment of the integrity of the fascial closure.

Adult↗