A Haitian in Connecticut

Bon jour, monsieur taxi driver

Here are my pennies and a fiver

I hate to break your reverie

But are you ready to deliver me to my destiny?

Long ago you were a refugee escaping calamity in Haiti

Eager to earn a living on the streets of Connecticut

Five years since fleeing from the western tip of an island and living in a land renowned for its glut

You tell me stories of waking up on a dirty mattress drenched in sweat

Desperately trying to figure out if your family in Port-au-Prince can be fed

When the earthquake hit your home in Hispaniola

Killing perhaps 200,000 people and flattening your home like a demonic steamroller

The world stopped to commiserate for a second

Humanitarian aid arrived and promises of change beckoned

Now, after roving from Pontius to Pilate

Your family back in Haiti sound desolate

Expressing the mournful sentiment

That billions of dollars failed to deliver enough of the basics such as latrines for excrement

Of course, you have every reason to remain proud and even vehement

After all, the “Pearl of Antilles” has had to pay a heavy price for any advance

Including blood and a fortune in cash to secure their freedom from France

The strength of Toussaint L’Ouverture is embedded in your DNA

Why is it then that depression and alcohol and corruption hold sway?

When the world loses interest

It will be up to Haitians to climb the infrastructure Everest

So, after clucking my tongue in sympathy at your sad story

My attention has been drawn away to a robbery at a nearby armory

Regretfully, this is the transparent world we live in today

Where talk is cheap, and few people care about painstakingly rebuilding a country, come what may.

Decontamination strategies to curb hospital-acquired infections

Hi everyone,

TB is the leading cause of death in South Africa and drug-resistant TB continues to be a problem, particularly in the province of Kwazulu Natal.  Curbing hospital-acquired infections such as drug-resistant TB may be one aspect of a multi-pronged strategy aimed at controlling the spread of this infectious killer. I blogged about this topic on The Norwalk Patch and am reposting the information here:

While there has been a 45% decrease in tuberculosis death rates since 1990, the growing crisis of drug-resistant tubercle bacilli (480,000 new cases of multi-drug resistant TB in 2013), high mortality rates (1.5 million deaths out of 9 million diagnosed TB cases in 2013), and ongoing HIV/TB co-infected cases (360,000 in 2013) persist across the globe. The post-2015 End-TB strategy from the World Health Organization involves three tiers i.e., integrated, patient-centered care and prevention, bold policies and supportive systems, and intensified research and innovation.

Appropriate disinfection and decontamination of hospitals, clinics, and other medical centers to reduce the prevalence of this airborne pathogen will be an important aspect of any integrated patient-centered care and prevention strategy. The merits and perils of automated systems such as hydrogen peroxide vapor and ultraviolet light disinfection systems to reduce the impact of hospital-acquired infections are discussed in Automated Technologies for Patient Room Disinfection and Decontamination of Biosafety Level 4 Infectious Agents, Including Ebola Virus.

Addressing a need by printing prosthetics (first appeared in The Norwalk Patch)

Losing a hand, digits, or limbs can sometimes be viewed as unfortunate accidents or the traumatic consequences of life in war-torn regions. However, estimates suggest that major (amputation above the elbow, below the elbow, above the knee, below the knee, or the foot) or minor (amputation of the hand, fingers, or toes) limb loss occurs more often than we realize in the general population. According to separate reports, almost 2 million people lived with limb loss in the USA and hospital expenses associated with amputations totaled $8.3 billion in 2009. A small fraction of the cost could possibly be attributed to treatment of 1,715 US soldiers (as of December 2012) who lost limbs in Iraq or Afghanistan or congenital limb deficiencies. Based on a 2008 report, the remaining amputations were mostly caused by vascular disease (54%) – including diabetes and peripheral arterial disease – trauma (45%) and cancer (less than 2%). The percentage of non-traumatic lower limb amputations in diabetics increased to more than 60%, according to data from the 2011 National Diabetes Fact Sheet. Moreover, it is estimated that up to 55% of diabetic amputees will require amputation of the second leg within 2‐3 years.

Globally, one amputation occurs every 30 seconds. In addition, The International Society for Prosthetics and Orthotics and the World Health Organization (WHO) estimated that at least 0.5% of populations in developing countries and other regions are in need of prostheses or orthotics and related services. Prosthetic devices can range from basic walking support for lower-limb amputees to state-of-the-art devices mimicking human movement, enabling amputees to navigate rough terrain, climb stairs, or perform athletic feats. Physical and societal obstacles, leadership and governance, service delivery, human resources, production, and affordability are key barriers to assisting amputees.

While the WHO made suggestions to overcome these barriers, it means that in practice considerable time would have elapsed before people like Richard Van As in South Africa and limbless children in the Sudan obtained access to affordable prostheses. Van As, a master carpenter, lost four of his fingers in a work accident and collaborated with others to make mechanical fingers (using a 3D printer). Richard has since expanded theRobohand project to making mechanical fingers for people with congenital deformities or who have lost their digits. Similarly, Not Impossible’s Mick Ebeling gave hope to Sudanese child amputees (through Project Daniel) by setting up a 3D-printing prosthetics lab and facility in that country.

State-of-the-art prosthetics may simply be beyond the pocket books of many amputees. Could Project Daniel and the efforts of the Open Prosthetics Project be replicated in other low- or middle-income countries where disabled people may have inadequate health insurance? In those cases, low-cost 3D-printers (such as a prototype currently in development in Togo or the printrbotPLUS) could conceivably be used to print replacement digits while awaiting evaluation by a medical professional. While amputees in poor countries and elsewhere await government support, ordinary folks will likely continue to fill an important need and inspire others through their actions.

Enabling the future by printing prosthetics

Passionate people fulfilling a good mission are not the immediate stuff of headlines. However, a group of volunteers deserve a shout-out for 3D-printing prosthetics that can help disabled people across the globe. Read more about them here: http://enablingthefuture.org/

Reading about them, also reminded me of a 3D-printing show that I summarized some time ago in The Norwalk Patch:

MacGyver, an American action-adventure hero from an eighties TV-series, usually solved his problems with duct tape and a Swiss-army knife. Today, designers and inventors can replicate these objects and numerous other products with the aid of three-dimensional (3D) scanners and 3D-printers. Motion-sensing devices such as Microsoft’s Kinect, a webcam-style add-on computer peripheral, or Fuel3D’s handheld 3D-scanner (one of a growing number of devices using lasers, lights, or x-rays), can be used to capture the geometry of physical objects, including oneself. The recent 3D Printshow in New York featured the genius of Joshua Harker, a pioneer in art and 3D-printing, and different companies willing to transform the ideas of at-home tinkerers into digital models. A quick Google search revealed that 3D-scanners can range from $400 to almost $85,000. It might also be worth waiting for the release of a functional 3D-scanning accessory for the iPad. According to Wired magazine, average Joes may soon be able to capture the dimensions of a room and generate 360-degree panoramic photos or create any other digital representation of the real world using the Structure Sensor.

Alternatively, 3D-aficianados (architects, designers, builders, makers and engineers), may use SketchUp, Adobe Photoshop CC (which has buttons for 3D-printing) or other appropriate software to create digital models from scratch. Others may prefer downloading shared files from Thingiverse. The next step for the cost-conscious inventor would be to find a third-party outlet or reasonably-priced machine to transform computer files into physical models. Shapeways, 3D Hubs, and i.Materialise belong to the cottage industry of 3D-printing services offered at a reasonable price to creative types. “Soup-to-nuts” consumers may also wish to read 3D Printing for Dummies or take classes at places like 3D Heights to gain insights about the printing process. Typically, an object is printedby repetitively solidifying or binding a liquid or powder in horizontal cross-sections where solid material is desired. The layering is repeated until the entire object is completed throughout its vertical dimension. Side-by-side comparisons of 24 3D-printers can be viewed on the TopTenReviews site and kits for assembling affordable printers are in development or already available e.g., printrbot.

Printing ideas into reality at the push of a button can unlock limitless creativity and also open up a Pandora’s Box of security and copyright infringement concerns. Fortunately, the US Senate just approved a 10-year extension on a ban on plastic guns invisible to metal detectors. Applying copyright infringement laws to this evolving technology may prove tricky, but John Hornick may be on to something in stating that iTunes-like models for copyrighted computer-aided design files could potentially make printing legal copies easy and economical.

 

Through the looking glass with Da Vinci and Carroll

(First appeared in the Rockefeller University Newsletter and the Norwalk Patch):

Have you ever started a project with great gusto only to be distracted, or to switch to something else midstream? Fear not. You are in good company when it comes to an inability to complete projects. Leonardo Da Vinci, arguably the world’s most famous polymath, needs no introduction in terms of his achievements, but was also known for having great difficulty completing tasks. Then again, few people would quibble with having a painting like The Adoration of the Magi on their list of unfinished works.

Today, Da Vinci has been immortalized in the world of fiction by the author, Dan Brown, as a code-writer rather than immersed in scientific, engineering, and artistic endeavors. Who knows? Maybe Brown subconsciously drew some of his inspiration from Da Vinci’s well-known mirror-writing skills. Mirror-writers, mostly left-handers or ambidextrous people, are able to write in the opposite direction and backwards to that of normal writing, so that the text can only be easily read when held up to a mirror. Some people, mostly children in the early developmental stages, or patients with neurological or psychological disorders, may engage in partial mirror writing, i.e. letters or numerals written in reverse appear occasionally in otherwise normal writing.1 There are also anecdotal reports of possible genetic links and a surprisingly high prevalence of mirror writing among normal people. 2

Habitual mirror-writers like Da Vinci have been the subject of numerous scholarly works on neurological phenomena. They are often compared with transient mirror writers like Reverend Charles Dodgson aka Lewis Carroll, author of the children’s classics,Alice in Wonderland and Through the Looking Glass, and What Alice Found There. Carroll occasionally penned “looking glass letters,” as in the poem, Jabberwocky, presumably as an artistic device to entertain children. Carroll’s contrived writing appears far removed from the faithful mirror images emblematic of Da Vinci’s writings in his notebooks, and probably involved different neural mechanisms or other causes.3

It may be fashionable to group unusual behaviors of famous figures in categories marked “disease” or “disorder,” however, there is no doubt that the origins and content of Da Vinci and Carroll’s writings will continue to fascinate scholars and laymen alike.

References
1. Nakano, M., T. Endo, and S. Tanaka, A second Leonardo da Vinci? Brain Cogn. 2003, 53(1) 9-14.
2. Schlott, G.D., Some neurological observations on Leonardo da Vinci’s handwriting. J Neurol Sci. 1979, 42 (3) 321-9.
3. Larner, A., The Neurology of ‘Alice.’ ACNR 2006, 4(6) 35-36.

Lung cancer

First appeared in the Norwalk Patch:

In 2006, Dana Reeve – actress, activist, and non-smoker – died of lung cancer. In 2009, Valerie Harper – actress and “Dancing with the Stars” contestant – was diagnosed with lung cancer that has since metastasized to the brain. They are the famous faces of a disease that is the leading cause of cancer deaths. Lung cancer is mainly caused by smoking, although prior lung disease, genetic predisposition, and environmental agents are also risk factors. Patients can be diagnosed with small-cell lung cancer disease ([SCLC]:~14%), mesothelioma (age-adjusted incidence: 0.9 per 100,000 people, but disease has increased 50% between 1977 and 2008) or, as in the case of Valerie Harper, with non-small cell lung cancer ([NSCLC]; 85%). NSCLC tumors are further stratified into squamous-cell, adeno-, and large-cell-carcinomas. If diagnosed prior to metastasis, the 5-year survival is more than 50%. However, the majority of patients are diagnosed with advanced disease, with a 5-year survival of 16 – 18% for NSCLC and 5% for SCLC.

Effective screening to identify lung cancer in the early stages remains the holy grail of disease management. The US Preventive Services Task Force’s has recommended annual low-dose computed tomography (CT) screening for high-risk individuals, ages 55 through 79, who have a 30 pack-year history of smoking or who have quit in the past 15 years. The National Framework for Excellence in Lung Cancer Screening and Continuum of Care, developed by the Lung Cancer Alliance, is geared towards screening based on best practices. Researchershave cautioned that low-dose CT-screening is associated with a propensity for over-diagnosis and possibly inappropriate treatment. This situation could potentially be remedied with the validation of biomarkers distinguishing between indolent, clinically insignificant tumors and aggressive disease. The future development of non-invasive biomarker kits (to accurately differentiate between clinically insignificant and aggressive early disease states), analogous to the non-invasive, circulating tumor DNA kits currently being evaluated for the overall detectionof stage II-IV lung cancer, would be a welcome step in this regard.

Individualized treatment will depend on the stage of the disease, histologic sub-type, and molecular profile. Ideally, validated biomarkers would guide treatment decisions. Most lung tumors can be further classified according to ‘driver mutations’ in signaling molecules e.g., about 23% of adenocarcinomas harbor epidermal growth factor mutations and the frequency for some of the other known mutations range from 0.2% (N-RAS, neuroblastoma RAS viral oncogene homolog) to 6% (EML4-ALK, echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase-gene-fusion) and 25% (KRAS, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), respectively (1).

While chemotherapy may favor certain patients, approved genotype-directed therapies have been shown to be initially effective in patients harboring defined mutations (compared to individuals carrying the wild-type gene). However, drug resistance has emerged as a major contributor to failure of targeted therapies and standard chemotherapy (2). The development of second-, or third-generation tyrosine kinase inhibitors and other novel agents with greater potency has been spurred, partly, by the need to overcome acquired drug resistance (2).  Ceritinibis one example of a promising agent associated with progression-free survival (PFS) of patients with advanced ALK-rearranged NSCLC (median PFS = 7 months, [95% CI, 5.6 to 9.5] based on phase I data; patients included those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK) (3).

In addition, the use of immunotherapies to successfully treat melanoma and renal cancers, has led to the development of agents that are also showing promise in lung cancer management. These immune checkpoint inhibitors target a host of immunosuppressive mechanisms likely to be unique to a given patient’s cancer. Depending on the therapy and study phase, 2-year overall survival rates up to 24% have been reported (4). Separate studies with promising investigational agents are currently entering preclinical or clinical accrual phases.

References

1.    Cheng L, Alexander RE, Maclennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25(3):347-369.

2.    Wangari-Talbot J, Hopper-Borge E. Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma. J Can Res Updates. 2013;2(4):265-282.

3.     Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2014;370(13):1189-1197.

4.     Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control. 2014;21(1):80-89.

How to hack a life

Start with a background check

Cherry-picking juicy tidbits left from enemies willing to turn a life into a wreck

Amplify mistakes with poisonous gossip rising to a crescendo

Plant cameras and microphones to record frustration and innuendo

Feign innocence to gain trust, then steal keys to invade a home,

Mock laws and instill fear wherever the victim dares to roam.

Organize accomplices eager to participate in a digital lynching,

Aroused at the chase, even as the quarry keeps flinching.

Then flip the narrative,

By turning the victim into a villain, and quarantining that person an imperative.

Manipulate the metadata with distortions

Until the victim is straight-jacketed in a labyrinth of mental contortions.

Then blame everyone else, especially the victim, for showing pain.

View a soul’s destruction as a teachable moment and repeat the process all over again.

 

Antibiotic resistance

Antimicrobial resistance is a pressing healthcare issue, resulting in at least 23,000 direct deaths every year in the United States [1]. The problem is exacerbated by the spread of multidrug-resistant organisms such as Enterococcus spp., Klebsiella spp., andStaphylococcus aureus [2]. In addition, treating multidrug-resistant Enterobacteria e.g.,Pseudomonas aeruginosa and Acinetobacter baumannii, and other Gram-negative bacilli are increasingly common problems in healthcare settings. Both appropriate and inappropriate use of antibiotics in humans and animals are major drivers for the global spread of antibiotic-resistant microbes. In addition, inadequate measures to control the spread of infections and safety concerns may account for the far-reaching effects of antibiotic resistance [3].

Depending on the type of resistance and associated expenses, conservative estimates of the annual economic burden to the United States alone could be as high as $55 billion ($20 billion in health service costs and $35 billion in lost productivity) [4]. Moreover, antibiotics require 72 candidates to yield an approved agent at a cost of  up to $800 million (other drugs require 15 candidates to yield one medication approved by the United States Food and Drug Administration) [5]. However, a world without effective therapeutics to combat increasing infectious diseases, infectious complications associated with other diseases, and the inevitability of drug-resistant bacteria as therapeutic applications of antibiotics become more widespread is unthinkable [6]. The search for a “magic bullet” to treat bacterial resistance i.e., mutations attributable to heritable genetic elements, is a necessity and will have to encompass the development of new medicinal chemistries to eradicate persisters (phenotypic variants that survive prolonged exposure to a bactericidal antibiotic despite being genetically susceptible [7]) that are frequently responsible for recalcitrant infections [8].

Targeted removal of pathogens with the aid of the immune system requires developing new compounds or combinations of existing antibiotics and other therapeutic regimens to shut down or bypass known bacterial resistance pathways. Bacterial strategies include horizontal transfer of resistance-conferring genes [9, 10], cell wall destruction, membrane alterations, restricted drug penetrance, and the presence of multidrug efflux pumps [8, 9]. Milestones during the golden era of antibiotic discovery include the identification of the aminoglycoside, streptomycin, in 1943 and the discovery of the quinolone, ciprofloxacin, in 1961. Aminoglycosides and fluoroquinolones can kill quiescent cells, while β-lactams such as penicillin (discovered in 1928) inhibit growing cells [8]. While there are about 200 conserved essential bacterial proteins, only a few targets have historically been exploited for drug discovery [8]. Three resistance pathways are targeted by representatives from the most successful antibiotic classes i.e., fluoroquinolones, β-lactams, and aminoglycosides inhibit DNA gyrase or topoisomerase, cell wall synthesis, and the ribosome (composed of 30s and 50s subunits) respectively [11]. Moreover, biofilms – the predominant bacterial matrices found in hospitals [12]– exhibit increased resistance to antimicrobial agents compared with planktonic cells. The amplified presence of persisters, one of five known mechanisms associated with biofilm antibiotic tolerance [13], may contribute to bacterial recalcitrance and relapsing infections [14]. Cell-intrinsic mechanisms such as toxin-antitoxin modules or cell-extrinsic factors such as chemical signals or reactive oxygen species may also contribute to the physiological basis of persistence i.e., a transitory growth arrest [7].

To overcome bacterial survival strategies and improve discovery hit rates, scientists will need to develop new screening technologies, medicinal chemistries, and devise rapid diagnostic techniques for etiologic agents. Synthetic tailoring of core chemical structures – the mainstay of novel antibiotic prospecting [6] –led to the development and significant use of numerous antibiotic classes e.g., penicillins, cephalosporins, macrolides, glycopeptides, tetracyclines, and sulfa drugs. However, the pace of discovery has slowed, with only two antibiotic classes (fluoroquinolones and oxazolidinones) being developed in the last five decades [8]. While additional modifications of the tetracycline and quinolone classes as well as the introduction of a pro-drug scaffold hold promise [8], it is unlikely that tailoring of antibiotic scaffolds can continue in perpetuity. New synthetic compounds used in combination with standard therapies may minimize resistance or enable the destruction of more than one bacterial target [8].

Screening

Boosting the antibiotic arsenal requires screening existing chemical libraries for overlooked compounds, identifying cryptic biosynthetic pathways in antibiotic-producing strains that may yield useful metabolites [8, 15], evaluating novel synthetic and natural sources for potentially successful antibiotics, and developing reliable innovative discovery platforms geared towards targeted therapies with minimal effects to host cells [8]. Rapid identification of the etiologic agent is a prerequisite for the development of such targeted therapies e.g., a rapid diagnostic test developed for methicillin-resistant Staphylococcus aureus will enable the identification of selective agents against this clinically important pathogen [8]. Chemical analysis of a lead compound’s mode of action and potential resistance mechanisms would be the next step. Reference databases of proprietary targets will be useful in assigning mechanisms of action to lead compounds. However, a limitation of this approach is the number of compounds required for successful mechanism-of-action classifications ─ a minimum of 5 to 6 compounds per class [16]. Furthermore, an understanding of interactions between drugs and resistance mutations  [10] could guide the selection of combination therapies aimed at increasing the number of hits in order to eradicate a targeted pathogen. Ideally, any screening technology should also identify non-essential pathways that may contribute to resistance such as drug efflux pumps or enzymes that could destroy the compound.

Currently the paucity of medications that can effectively penetrate bacterial cells (Gram-negative bacteria are very effective at keeping out drugs [8]) may necessitate rescreening existing chemical libraries of promising lead compounds with modified “Lipinski’s rule of 5”(physicochemical properties that influence oral bioavailability) guidelines. Traditional libraries were typically derived synthetically or from natural sources and screened using rules that are not applicable to antimicrobials and focused only on assessing molecular properties pertaining to oral bioavailability [8]. Rules of bacterial penetration could conceivably be developed based on in vitro tests using compounds known to effectively permeate bacteria. Appropriate tests of focused libraries in situ could also eliminate compounds with poor serum binding, instability or poor tissue distribution in vivo [8].

A screen performed by nature outnumbers currently available synthetic compounds. Lipopeptide (daptomycin), glycylcycline (tegicycline), streptogramin  (pristinamycin), glycopeptide (vancomycin), macrolide (erythromycin),, aminoglycoside (streptomycin), phenylpropanoid (chloramphenicol), β-lactam (penicillins, cephalosporins, carbapenems, monobactams),  and polyketides (tetracycline) core structures have all been constructed from natural sources [17]. Uncultivated organisms (99% of bacterial species are not cultivable by traditional methods [18]), marine [17], mammalian [19], reptilian [20], fungi and plant sources are among the important reservoirs for ideal antibiotics i.e., pro-drugs converted by intra-cellular bacterial enzymes into reactive compounds capable of killing persisters and actively dividing cells [8].

The probabilities of discovering new compounds in old libraries were estimated to be around 10-5 to 10-4 [8]. Leads for combination therapies could potentially emerge from pre-designed bacterial silencer RNA (siRNA) libraries as in the case of the discovery of platensimycin and platensin in the Merck 245 siRNA collection [6, 8]. Although the clinical utility of platensin and platensimycin have been questioned [6, 21], it is conceivable that lead compounds discovered in gene-knockdown collections could re-sensitize bacteria to approved antibiotics when used synergistically in selected combination therapies [6]. Metagenomics of cultivable and uncultivable organisms may yield further lead compounds and predict the emergence and epidemiology of antibiotic resistance e.g., the comprehensive antibiotic resistance database is a unifying bioinformatics compilation of 3411 resistance genes from disparate sources designed to exploit the power and falling costs of next-generation DNA sequencing technologies [22].

A significant problem stalling the drug discovery pipeline is the question of which compounds are worth further characterization and purification. Sensitive bioassays using feasible test organisms could be effective in identifying novel antibiotics e.g., the differential susceptibility of Bacillus subtilis test and parent strains provided an important secondary screen for the evaluation of potential bacterial RNA polymerase inhibitors from a primary screening of actinomycete isolates [15].

Other strategies

Ongoing challenges in the treatment of infectious diseases include the specter of secondary infections e.g., Clostridium difficile-associated diarrhea and candidiasis and collateral damage to bacterial mutualists [23]. Thus, alternative antimicrobials or therapies that augment the host response to infectious diseases are also currently under investigation.

Antimicrobial peptides (AMPs), typically 20 to 50 amino acid residues long, are important components of the innate immune system and may be used to overcome resistance challenges from different microorganisms, including Gram-positive and Gram-negative bacteria, fungi, and viruses [5]. Natural AMPs from bacteria usually kill target pathogens with a high potency (pico- to nanomolar range) and specificity [24] via protein- or non-protein-mediated mechanisms [5]. Since resistant strains have been observed in preclinical trials, it will be important to undergo an analysis of the co-evolution of bacterial resistant strains during the development of AMPs [5]. Other strategies currently being studied include phage and photodynamic therapies, probiotics, honey therapy, maggot therapy, herbal medicines, statins, vaccines, and fecal transplants [23, 25]. In the latter case, the objective is to shift the diseased microbiome of patients to a “healthier” alternative stable state [23]. Fecal transplantation has been successful in resolving the symptoms of recurrent C. difficile-associated diarrhea [26]. General use of active microbial repopulation strategies will, however, require proof of efficacy and pharmaceutical-grade products [23].

References

  1. (US Department of Health and Human Services) Centers for Disease Control and Prevention. Untreatable: Report by CDC details today’s drug-resistant health threats.2014  [cited 2014 Jan]; Available from: http://www.cdc.gov/media/releases/2013/p0916-untreatable.html.
  2. Boucher, H.W., et al., Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America.Clin Infect Dis, 2009. 48(1): p. 1-12.
  3. (US Department of Health and Human Services) Centers for Disease Control and Prevention. Antibiotic/Antimicrobial Resistance: Threat Report 2013. 2014  [cited 2014 Jan]; Available from: http://www.cdc.gov/drugresistance/threat-report-2013/.
  4. Smith, R. and J. Coast, The true cost of antimicrobial resistance.BMJ, 2013. 346: p. f1493.
  5. Tavares, L.S., et al., Strategies and molecular tools to fight antimicrobial resistance: resistome, transcriptome, and antimicrobial peptides.Front Microbiol, 2013. 4: p. 412.
  6. Walsh, C.T. and T.A. Wencewicz, Prospects for new antibiotics: a molecule-centered perspective.J Antibiot (Tokyo), 2013.
  7. Balaban, N.Q., et al., A problem of persistence: still more questions than answers?Nat Rev Microbiol, 2013. 11(8): p. 587-91.
  8. Lewis, K., Platforms for antibiotic discovery.Nat Rev Drug Discov, 2013. 12(5): p. 371-87.
  9. Alekshun, M.N. and S.B. Levy, Molecular mechanisms of antibacterial multidrug resistance.Cell, 2007. 128(6): p. 1037-50.
  10. Palmer, A.C. and R. Kishony, Understanding, predicting and manipulating the genotypic evolution of antibiotic resistance.Nat Rev Genet, 2013. 14(4): p. 243-8.
  11. Coates, A., et al., The future challenges facing the development of new antimicrobial drugs.Nat Rev Drug Discov, 2002. 1(11): p. 895-910.
  12. Percival, S.L. and P.G. Bowler Biofilms and Their Potential Role in Wound Healing. Wounds 2004, 16 (7) Medscape Multispecialty, 2004. 7.
  13. Lazar, V. and M.C. Chifiriuc, Medical significance and new therapeutical strategies for biofilm associated infections.Roum Arch Microbiol Immunol, 2010. 69(3): p. 125-38.
  14. Lewis, K., Multidrug tolerance of biofilms and persister cells.Curr Top Microbiol Immunol, 2008. 322: p. 107-31.
  15. Tanaka, Y., et al., rRNA (rrn) operon-engineered Bacillus subtilis as a feasible test organism for antibiotic discovery.Antimicrob Agents Chemother, 2013. 57(4): p. 1948-51.
  16. Hutter, B., et al., Prediction of mechanisms of action of antibacterial compounds by gene expression profiling.Antimicrob Agents Chemother, 2004. 48(8): p. 2838-44.
  17. Hughes, C.C. and W. Fenical, Antibacterials from the sea.Chemistry, 2010. 16(42): p. 12512-25.
  18. Piel, J., Approaches to capturing and designing biologically active small molecules produced by uncultured microbes.Annu Rev Microbiol, 2011. 65: p. 431-53.
  19. Wang, J., et al., Ancient Antimicrobial Peptides Kill Antibiotic-Resistant Pathogens: Australian Mammals Provide New Options.PLoS ONE, 2011. 6(8): p. e24030.
  20. Samy, R.P., et al., Snake Venom Proteins and Peptides as Novel Antibiotics Against Microbial Infections.Current Proteomics, 2013. 10(1): p. 10-28.
  21. Brinster, S., et al., Type II fatty acid synthesis is not a suitable antibiotic target for Gram-positive pathogens.Nature, 2009. 458(7234): p. 83-6.
  22. McArthur, A.G., et al., The comprehensive antibiotic resistance database.Antimicrob Agents Chemother, 2013. 57(7): p. 3348-57.
  23. Lemon, K.P., et al., Microbiota-targeted therapies: an ecological perspective.Sci Transl Med, 2012. 4(137): p. 137rv5.
  24. Hassan, M., et al., Natural antimicrobial peptides from bacteria: characteristics and potential applications to fight against antibiotic resistance.J Appl Microbiol, 2012.113(4): p. 723-36.
  25. Bourlioux, P., [Which alternatives are at our disposal in the anti-infectious therapeutics face to multi-drug resistant bacteria?].Ann Pharm Fr, 2013. 71(3): p. 150-8.
  26. Cammarota, G., G. Ianiro, and A. Gasbarrini, Fecal Microbiota Transplantation for the Treatment of Clostridium difficile Infection: A Systematic Review.J Clin Gastroenterol, 2014 (e-pub).

Porsche

This midlife crisis fantasy appeared in The Norwalk Patch in 2012 for the first time. Enjoy!:

Summer means different things to different people. It could mean booking a ticket to see Mike Love belting out Beach Boys’ classics, dragging out the rock guitar from the attic to play Grateful Dead cover songs at the Tuscan restaurant (New Canaan), pontificating about the consequences of Justice Roberts’ deciding healthcare vote for the masses or, flipping between the extremes of watching young studs duking it out for the affections of the singer,  Rihanna, and Katie Holmes duking it out in court with soon-to-be-ex-husband, Tom Cruise,  over custody of their daughter, Suri. What is a nation  to do when the chattering classes recite the eulogy to the  “American Dream,” and beach reading consists of Rielle Hunter feeling the need to regale the stressed-out masses with more details about the Edwards’ marriage?

If you are a middle-aged guy without any prospects, marginalized by society and your own mistakes, it might just be time to escape into a world of fantasy. Forget about the fact that you are a fiftysomething graybeard way behind on child support (an appearance on Judge Judy looking suitably contrite might take care of those woes). Forget about the fact that your disability check will not be forthcoming, because some details got lost between filing a claim for an accident and the paperwork prepared by the lawyer you found on craigslist. Forget about the fact that you are now living on a wing-and-a-prayer in a room with other older adults, nursing your injuries with cheap vodka-laced juice and awaiting Obamacare in 2014. If society has written you off, your self-esteem is in the commode, and a midlife crisis is churning through your veins, it is time to reach for the motorcycle that survived the Great Depression, ie, the Harley-Davidson. It is time to hit the open road. Goodbye Connecticut, hello Florida.

Perhaps you had heard about that Shangri-La saloon in Florida from other members of your crew of outcasts. Perhaps you panic as you finally arrive at this hallowed destination, order a beer, and politely decline the attentions of  widows of a certain age. And then she arrives. The Madonna of Shangri-La. She is the twentysomething party-girl renowned for fulfilling the fantasies of every middle-aged dreamer. Her name/pseudonym, aptly enough, is Porsche. Two blissful days at a five-star hotel and several thousand dollars later (your kids’ inheritance money, of course), she steers you towards her uncle’s Porsche dealership. The uncle, obligingly, lets you take one of the cars out for a test drive. You contemplate purchasing the car to keep Porsche (the girl and the dealership) happy. Suddenly you feel young again.

One of your children (the responsible one who is just a few years older than Porsche) rushes to your side to bring you to your senses.

Then Porsche disappears (the girl, not the dealership). The dealership owner starts acting like Tony Soprano and you hightail it out of there back to Connecticut. Your long-suffering friends and family listen to your story. They laugh and add another burger to the grill. Ah, to be an ageing “boomer” during the summer of 2012.