Mortara Instrument’s new family of Surveyor WiFi telemetry solutions is designed to offer diagnostic-quality ECG acquisition and to work on the existing WiFi network, with no need for a dedicated network infrastructure. Its outstanding features have been the key decision factors for Policlinico San Donato (Milan, Italy), one of the top-ranking centers for the study and treatment of cardiovascular diseases, to select Mortara telemetry system.

Mortara designed the Surveyor S4 solution based on three main criteria: cost saving, coverage and clinical excellence.

Cost is a major priority of today’s healthcare professionals and also one of Mortara’s top concerns. The Surveyor S4, thanks to its advanced design, can operate on existing WiFi infrastructure to broadcast physiological signals. It eliminates the cost of a proprietary antenna network, which is required by traditional telemetry systems. Removable, rechargeable batteries allow a lower ecological footprint than disposable batteries, while also reducing running costs.

Coverage (i.e. the areas where the patients can be monitored) is also revolutionized with the Surveyor S4; the use of WiFi technology allows patients to be monitored virtually wherever the WiFi signal is available throughout the facility. This means more freedom for the patient, but also extends patient monitoring to more departments; the ability to clinically monitor and evaluate patients is enhanced without additional beds being added to the traditional telemetry area.

Mortara takes pride in delivering clinical excellence. VERITAS^TM is the suite of algorithms created by Mortara to analyze ECG signals. The Surveyor S4 family includes the latest algorithms that provide clinicians with absolute reliable data. From basic to lethal arrhythmias, VERITAS is the ideal companion for clinicians. In addition, all Surveyor S4 mobile monitors offer diagnostic quality acquisition; combined with the true 12-lead ECG amplifier, they offer best-in-class 12-lead ST segment analysis. True 12-lead ECG monitoring allows physicians to detect early ST segment changes and obtain a complete evaluation of the cardiac profile of the patient, without additional tests.

Founded in 1969, IRCCS Policlinico San Donato is part of an 18-hospital network that provides over 5,000 beds, and is also host to the Medicine School of the University of Milan. The clinical arrhythmology and electrophysiology ward, run by Professor Carlo Pappone, is one of the international excellence centers for the treatment of all types of cardiac arrhythmias.

Atrial fibrillation, Brugada syndrome, Wolff-Parkinson-White (WPW) syndrome, and cardiac electro-stimulation are among the main research fields. In particular, the research on, and treatment of, supraventricular arrhythmias is a primary focus and area of expertise for this group of clinicians, as testified by the number of publications on international top-ranking journals, and directly witnessed by the large population of patients who have already successfully undergone trans-catheter ablation procedures.

Given the outstanding reputation of his center, Professor Pappone has chosen Mortara as the best-in-class partner in order to deliver excellent diagnosis and treatment.

Policlinico San Donato is one of the many centers where the Mortara monitoring solutions have been adopted and that every day helps to improve healthcare throughout the world.

In April 2011, the World Health Organization (WHO) warned that indiscriminate use of antibiotics was giving rise to resistant ‘superbugs’ which could render the drugs useless. Three years later, it warned about the arrival of a ‘post-antibiotic era.’ In autumn 2014, US officials termed antibiotic resistance a threat to national security.
However, awareness of this challenge has been present for decades. In the early 1990s, ‘Newsweek’ dramatically highlighted the threat in a cover story titled ‘End of the Miracle Drugs.’ A few months later, ‘Time’ magazine followed up with a feature on the ‘Revenge of the Killer Microbes.’

Bug resistance too knows no frontiers
The Centers for Disease Control and Prevention (CDC) has estimated that resistant bacteria lead to 23,000 deaths in the US every year. In Europe, the ‘British Medical Journal’ has urged authorities to harmonize antibiotic prescribing practices in order to tackle resistance. In spite of little effect on patients’ recovery times, an EU-funded study called GRACE identified wide variations in antibiotic use. For coughs, for example, antibiotic prescribing by physicians ranged from 20% in some countries to 90% in others.
Nevertheless, according to a report in the ‘The New York Times’ at the end of 2014, efforts to crack down on “inappropriate antibiotic use in the United States and much of Europe have been successful,” with prescriptions dropping from 2000 to 2010. Such a drop has, however, been “more than offset” by growing use in the developing world, according to ‘The Times’.
Indeed, like bugs themselves, drug-resistant bugs seem to know no frontiers.

Large emerging markets drive global drug sales
The ‘Times’ reports that sales of antibiotics for human consumption worldwide rose by 36% in the 2000-2010 period, with more than three-fourths of this increase accounted by the BRICS group of major emerging markets (Brazil, Russia, India, China and South Africa).
Such findings have been endorsed by an authoritative study, published in September 2015 by the Center for Disease Dynamics, Economics and Policy (CDDEP). The CDDEP report,  which has drawn up a global Resistance Map for antibiotics, found sharp growth in resistant bacteria in developing countries, notwithstanding much lower per capita use of antibiotics.

India: highest risk case
The respected journal ‘New Scientist’ has recently also covered the CDDEP report, singling out culprits as countries with growing wealth – “especially India,”… “where more people are demanding antibiotics for minor infections.”
Indeed, the CDDEP highlights the case of E. coli in contaminated water or food, where India shows the world’s highest rates of resistance to nearly every available drug. Other problems in India include MRSA, where isolates have shown prevalence rising sharply, from 29% in 2009 to 47% in 2014 and Klebsiella pneumoniae, which can cause fatal lung infections. In 2014, 57 per cent of Klebsiella pneumoniae samples tested in India were resistant to carbapenems, an antibiotic used as a last resort. By comparison, the figure six years ago was virtually zero.

Resistant bacteria and infants
Antibiotic resistance has an especially dramatic impact on Indian infants. According to the ‘New York Times’ article in December 2014, bacterial infections resistant to most known antibiotics led to the death of more than 58,000 newborns in India compared to the previous year. The head of Sir Ganga Ram Hospital, one of India’s top medical facilities, stated that such infections were unheard of just five years previously. “Now, close to 100 percent of the babies referred to us have multi-drug resistant infections,” he lamented.
Ironically, due to high rates of infant mortality, the Indian government has been encouraging women, sometimes with financial incentives, to deliver babies in hospitals. The programme seems to have worked. Within a decade, the share of babies born in hospitals has more than doubled to over 80%.
However, the government has spent little to increase hospital capacity. As a result, maternity wards are overcrowded, sometimes with two or three women per bed. Apart from overcrowding, many hospitals are unhygienic. A UNICEF survey of 94 district hospitals and health centres in the Indian state of Rajasthan found 78% lacked soap at hand-washing sinks, while 67% of toilets were unsanitary.

The impact of bacterial resistance is, however, not just confined to newborns. Resistant bacteria cost the life of Uppalapu Shrinivas, one of India’s most famous musicians, at the age of 45.
Indeed, according to Dr. Timothy R. Walsh, a professor of microbiology at Cardiff University, India is creating a “tsunami of antibiotic resistance that is reaching just about every country in the world.”

NDM1: New Delhi’s global export
Researchers have already tracked superbugs with the so-called NDM1 (New Delhi metallo-beta lactamase 1) genetic code, first identified in India. NDM1 makes bacteria resistant to almost all antibiotics, including carbapenems – the drug of last resort.
The first report about NDM1 was published in ‘Lancet Infectious Diseases’ in April 2011, and made headlines due to the fact that this was the same time when the World Health Organization warned about superbugs.
The ‘Lancet’ study was sponsored by the EU and reported that NDM1 was found in about one fourth of water samples in New Delhi, the Indian capital. The authors speculated that, since many Americans and Europeans travelled to India and Pakistan for elective medical procedures, it was likely the superbug gene could eventually spread worldwide.

Since then, NDM1 has been found in Europe, the Middle East, Japan and the United States. 
Meanwhile, back in India, what worries public health experts is “that the NDM 1 gene appears to have spread to germs that cause cholera and dysentery, two common and dangerous ailments in India.” In other words, it may be no exaggeration to say that the drug resistance problem is about to explode.

From toilet deficits to untreated sewage
The roots of the problem are complex. Bacteria spread relatively easily in India, since an estimated half of Indians defecate outdoors. Meanwhile, much of the sewage generated by the other half, who use toilets, is also left untreated. The result is expected: Indians have some of the world’s highest rates of bacterial infections – and resistance.
Cardiff University microbiologist Dr. Walsh says up to “95% of adults in India and Pakistan” carry bacteria that are resistant to ‘last-resort’ antibiotics such as carbapenems. By comparison, only 10% of adults in the Queens area of New York carry such bacteria.

The answer to no sanitation: use antibiotics, preventively
Ironically again, rather than building better infrastructure for sanitation, the response in India to growing bacterial infections has been to resort indiscriminately to antibiotics, which are often sold without a prescription. According to the December 2014 report in ‘The New York Times’, Indians collectively take more antibiotics than any other group of people.
Together, the lack of sanitation and overcrowding in hospitals may well have catalysed the superbugs. Doctors across India too have lent the crucial helping hand by responding to the hospital sanitation crisis through doling out antibiotics. In the Indian State of Haryana, for example, almost every baby born in hospitals in recent years has been injected with antibiotics – “whether they showed signs of illness or not,” Dr. Suresh Dalpat, deputy director of child health told ‘The New York Times’.
Completing the circle is the fact that the resistant bacteria, created by indiscriminate use of antibiotics, find their way into hospital sewage. As mentioned, much of this is untreated and dumped into canals and pits in nearby communities, leading to the infection of pregnant women, the delivery of ill infants – and more antibiotics.

A perfect storm
Though some Indian health experts believe drug-resistant bacteria to be largely confined to hospitals, some of India’s top neonatologists suspect the bacteria have begun “thriving in communities and even pregnant women’s bodies.”
“India has a perfect storm,” says Dr. Ramanan Laxminarayan, author of the CDDEP report. “You put all the things together and it’s this gigantic petri dish of experimentation that is resulting in highly pathogenic strains.”

Nevertheless, rushing to blame India alone (or India and other developing nations) for the growing drug resistance may not be helpful, or entirely accurate. Carbapenemases like NDM-1 have also been discovered elsewhere. For example, Klebsiella pneumoniae carbapenemase (KPC), currently the most common carbapenemase, was detected in the US in 1996 and has since spread worldwide. In addition, enterobacteriaceae which produce KPC have recently been reported as becoming common in the US.

Drug industry in India adds to the problem
In India, nevertheless, yet another growing area of concern seems to be loose compliance with regulations by Indian manufacturers of antibiotics. In early 2011, ‘Scientific American’ reported high levels of antibiotic resistance in bacteria downstream from a waste-water treatment plant in the southern Indian State of Andhra Pradesh.
Citing findings by a Swedish-led research team, the article noted that drugs in the effluent water from the plant were “sometimes equivalent to the high doses that are given therapeutically.” The antibiotic-rich water originated from the plants of 90 bulk drug manufacturers in the region.

The next wave: animal antibiotics in India
The other area for attention does not concern human use of antibiotics. Their overuse in chicken, pig and cattle farms in the US has also provoked the growth of resistant strains. Research has not only shown that “as much as half of antibiotic prescriptions in the United States are unnecessary,” but also that an estimated 80 percent of antibiotic sales remain directed at animals. 
In Europe, unlike the US, antibiotics for animal growth have been banned since 2006. However, their use in medicated feeds continues. This, in turn, fuels resistance to antibiotics, and not just through animals. One study in Poland discovered high levels of resistant bacteria in gardens, orchards and forest soils, largely due to manure from antibiotic-fed animals.

Unfortunately, India does not seem to be heeding such lessons. Its booming economy has led to rapid growth of industrialized animal husbandry, where antibiotic use is widespread. A science group in New Delhi found antibiotic residues in 40 percent of chicken samples.

In spring 2015, the New England Journal of Medicine’ reported the case of a patient with Stage IV metastatic melanoma – a disease considered close to untreatable. Although three growths in the skin had been surgically removed, one tumour under her left breast had grown deep into her chest wall. The 49-year old woman received a single treatment of an experimental combination of two drugs.
When she returned in three weeks for a second dose, the tumour had ‘kind of just dissolved’, according to Paul Chapman, the physician treating her at Memorial Sloan Kettering Cancer Center in the US.

Over one-fifth patients show complete response
The results were not an exception. 22percent of the 142 patients enrolled in the Memorial Sloan Kettering trial showed a complete response (with their cancer melting’ away), while 53percent had at least 80percent tumour shrinkage. However, there were downsides, too. Half the patients had side effects that were severe or life-threatening.
The drugs used in the trial were Yervoy (ipilimumab) and Opdivo (nivolumab). Approved by the Food and Drug Administration (FDA) for melanoma, the two belong to a small, new arsenal of drugs which supercharge the immune system to attack tumours. The process is known as immunotherapy, and brings together experts from several fields, ranging from oncology and immunology to cell biology and genomics.
Another well-known immunotherapy medication is Keytruda, sometimes called the Jimmy Carter drug’. Combined with surgery and radiotherapy, Keytruda has halted recurrence of melanoma in the former US president, although the disease had spread to his liver and brain.

Single drugs work too
One analysis of 4,846 advanced melanoma patients treated with Yervoy alone found 21percent still alive after three years. Patients who make it to three years ‘do not die of melanoma,’ according to James Allison of the MD Anderson Cancer Center in Houston, Texas, who is widely credited with pioneering modern immunotherapy.
Meanwhile, beyond melanoma, the combination of Yervoy and Opdivo has also shown extraordinary potential in bringing about remission in advanced stages of non-small-cell lung cancer, a leading cause of cancer-related mortality.

Leveraging the immune system
Leveraging the immune system to fight cancer, once little more than a medical dream, is becoming real. Using gene sequencing technologies to classify tumours, the immune system is now becoming primed with drugs and genetically-engineered cells.
The immune system itself consists of a biochemical network which defends the body against viruses, bacteria and other invaders. Cancer, however, finds ways to hide from the immune system, or block its ability to fight.
Immunotherapy seeks to help the immune system recognize cancer as a threat, and attack it.

The medical equivalent of atomic fission
At the moment, there are hundreds of immunotherapy clinical trials under way for almost all types of cancer, individually or combined with other treatments. Eventually, researchers hope to develop blood tests that allow for the early detection of cancer, determine which medicines can be effective and monitor the response in real time.
For some oncologists, immunotherapy is the medical equivalent of splitting the atom. John Heymach, a lung cancer specialist at MD Anderson, has described immunotherapy as a ‘complete game-changer.’ Several others concur. At an AACR press conference in 2015, Louis Weiner of Georgetown University observed: ‘We are in the middle of a revolution,’ and added that ‘I don’t think that is hyperbolic.’
The media too has leaped into the fray, latching on to the enticing concept of dissolving the tumours that physically embody one of humanity’s most intractable struggles against disease. Forbes’, for example, headlines an article: ‘Immune System Drugs Melt Tumours In New Study, Leading A Cancer Revolution.’

Checkpoint inhibitors
In practical terms, there are two contemporary approaches to immunotherapy.
The first (and more-widely used) method involves the use of drugs that block a so-called checkpoint’ mechanism used by cancers to shut down the immune system. This type of drug, known as a checkpoint inhibitor, is used to treat advanced melanoma, Hodgkins lymphoma and cancers of the lung, kidney and bladder.
The drugs work in 20-40percent of patients. In many such cases, the results are nothing short of spectacular, with prolonged remissions that persist, even after treatment is halted.

Checkpoint inhibitors harness T-cells, the white blood cells which could be described as the special force soldiers of the immune system. The T-cells can, however, run out of control and attack normal, healthy tissue, leading to autoimmune disorders like rheumatoid arthritis, Crohns disease and lupus. To avoid this, built-in brakes or checkpoints’ slow or shut down T-cells.
One type of checkpoint inhibitor stops T-cells from multiplying. Another weakens them and shortens their life span. The two drugs in the Yervoy-Opdivo study reported by the New England Journal of Medicine’ were both checkpoint inhibitors. Yervoy (ipilimumab) interferes with a molecule which switches off T-cells. Opdivo (nivolumab) prevents the death of T-cells.

Limitations with checkpoint inhibitors
Nevertheless, for the bulk of patients, checkpoint inhibitors do not show any results, or work for a while and then stop. In the Yervoy-Opdivo study, 126 of 142 patients did not see their cancer vanish entirely. One of the theories being researched to explain this setback is that other, to-be-discovered checkpoints are playing a role, and these would lead to new drugs that increase the scope of their effectiveness.
Meanwhile, harnessing an immune system in overdrive can also be very risky. As mentioned earlier, one out of two patients in the Yervoy-Opdivo study had side effects that were severe or life-threatening. In many cases, treatment for such patients needs to be discontinued.
Conversely, checkpoint inhibitors can also slow down vital glands such as the pituitary and thyroid, thus creating a lifelong need for hormone treatment. This can have an impact in other areas. For example, kidney transplant patients have suffered rejection after taking checkpoint inhibitors since the latter spurred their immune system to attack the grafted organ.
Checkpoint inhibitors can also take months to begin working, and sometimes cause inflammation that make scanner data show what may, confusingly, look like a growing tumour.

CART: personalized immunotherapy
The second approach involves highly personalized treatments known as CART, with the abbreviation arising from the use of a protein chimeric antigen receptor (CAR) to modify a T-cell, which are first removed from a patient, genetically altered to kill cancer, and then re-infused.
CARTs effectively synergize antibodies, which provide precision recognition of disease targets, with the power of T-cells. Unlike antibodies, however, the modified T-cells continue to multiply, serving as a living therapy.
In autumn 2013, researchers at Fred Hutchinson Cancer Research Center in Seattle launched a (preliminary) safety trial with a CART on a lymphoma patient, who had failed to respond to elevated doses of chemotherapy. It was the first trial of its kind to be conducted on a human. At the end of a fortnight, the patient was reported telling his physicians that the lymph nodes in his neck felt like ‘ice cubes melting.’

Beyond leukemia and lymphoma
CARTs have largely worked so far in cases of leukemia or lymphoma, albeit dramatically. However, Fred Hutchinson is also working on several other cancer types, including Merkel cell carcinoma, melanoma and several sarcoma subtypes.
Elsewhere, researchers at the University of Pennsylvania are working on a CART which targets mesothelin, a protein often encountered on the surface of tumour cells. Trials involve patients with serious ovarian cancer, epithelial mesothelioma, and pancreatic cancer.

Challenges with CART
Nevertheless, many practical challenges remain to be overcome with CARTs too. They require extensive research and refinement in the lab before patient trials. Production is also labour-intensive, requiring isolation of specific T-cells from a blood sample, followed by multiplication in an incubator and the use of a hemacytometer for counting, and then concentration in a centrifuge. Apart from fine-tuning their therapeutic effects, means to cost-effectively scale the technology will also be required to bring CARTs to market.
Like checkpoint inhibitors, CART therapy also has clinical limitations, even in its mainstay application in leukemia. 20-30percent of patients are not helped, and are likely to die.

Some way to go
In the final analysis, immunotherapy still has some way to go.
In spite of their often near-miraculous performance, immunotherapy drugs have worked in what is still a minority of patients.
Researchers are clearly aware that immunotherapy is unique, potent and extraordinary, but they cannot fully understand why – or yet control it adequately.

The risks of hype
Physicians also urge caution. Media-hype has led many patients to believe the age of chemotherapy is past. There are cases of unresponsive immunotherapy patients (or those suffering from unacceptable side effects) being switched back to chemotherapy, successfully. Though this may be due to a delayed effect of immunotherapy, it is too early to tell. Indeed, one explanation is that chemotherapy and immunotherapy may be working synergistically in such cases.

Industry too may need a reality check. Asset management companies like Piper Jaffray have forecast immunotherapy boosting the cancer treatment market to half a trillion dollars a year. This may of course face a collision with reality.
Yervoy costs over USD 120,000 ( Euro 110,000) for a four-course treatment, while Keytruda is billed at about USD 150,000 ( Euro 138,000) for a year. At current prices, the combination of Opdivo and Yervoy would result in an annual cost of USD 270,000 ( Euro 248,000). On their part, CART therapies may cost even more. How exactly these sums will be financed is indeed the trillion dollar question.