Take note of important signs and symptoms — from unexplained weight loss to sudden flashes of light — and know when to seek medical care.

by Mayo Clinic staff
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Chest pain, sudden loss of vision or speech, and severe abdominal pain require immediate medical attention — but what about more subtle red flags? It can be tough to know what to do. Here’s a list of seven signs and symptoms that merit attention.

No. 1: Unexplained weight loss

Losing weight without trying might sound like a dream come true, but in reality it can signal a health problem. If you’ve lost up to 10 percent of your weight during the past six months — for instance, 15 pounds (7 kilograms) if you weigh 150 pounds (68 kilograms) — consult your doctor.

An unexplained drop in weight could be caused by various conditions — including overactive thyroid (hyperthyroidism), diabetes, depression, liver disease, cancer or disorders that interfere with how your body absorbs nutrients (malabsorption disorders).

No. 2: Persistent or high fever

A fever isn’t necessarily a cause for alarm. Fever seems to play a key role in fighting infection. If you’ve had a fever for more than three days, however, get checked by your doctor. Persistent fever can signal a hidden infection, which could be anything from a urinary tract infection to tuberculosis. In some cases, cancerous (malignant) conditions — such as lymphomas — cause prolonged or persistent fevers, as can some medications.

If you have a high fever — 103 F (39.4 C) or higher — consult your doctor as soon as possible.

No. 3: Shortness of breath

Shortness of breath that feels more severe than what’s caused by a stuffy nose or vigorous physical activity could signal an underlying health problem. If you’re unable to get your breath, or you’re gasping for air or wheezing, seek emergency medical care. Feeling breathless when lying down also is a symptom that needs to be evaluated promptly.

Causes for breathlessness may include chronic obstructive pulmonary disease, chronic bronchitis, asthma, pneumonia, a blood clot in the lung (pulmonary embolism), as well as other heart and lung problems. Difficulty breathing can also occur with panic attacks — episodes of intense anxiety that can cause rapid heart rate, sweating, shortness of breath and other physical symptoms.

No. 4: Unexplained changes in bowel habits

What’s considered normal for bowel movements varies widely. Consult your doctor if you notice unusual or unexplained changes in what’s normal for you, such as:

• Bloody, black or tarry-colored stools
• Persistent diarrhea or constipation
• Unexplained urges to have a bowel movement

Changes in bowel habits could signal a bacterial infection — such as campylobacter or salmonella — or a viral or parasitic infection. Other possible causes include irritable bowel syndrome and colon cancer.

No. 5: Confusion or personality changes

Seek medical attention if you have:

• Sudden confused thinking
• Confusion about time or place (disorientation)
• Sudden problems with concentration or memory
• Sudden personality or behavior changes, such as becoming aggressive

Changes in behavior or thinking could be caused by many problems, including infection, anemia, low blood sugar, dehydration or mental health conditions. Sometimes medications contribute to confusion or personality changes.

No. 6: Feeling full after eating very little

If you consistently feel full sooner than normal or after eating less than usual, get checked by your doctor. This feeling, known as early satiety, also may be accompanied by nausea, vomiting, bloating, fever, and weight loss or gain. If so, be sure to tell your doctor about these signs and symptoms as well.

Possible causes of early satiety include gastroesophageal reflux disease, commonly known as GERD, and irritable bowel syndrome. In some cases, a more serious problem — such as pancreatic cancer — could be a factor.

No. 7: Flashes of light

Bright spots or flashes of light and other visual disturbances sometimes indicate a migraine. In other cases, sudden flashing lights could signal retinal detachment. Immediate medical care can help prevent permanent vision loss.

Technorati Tags: Chest Pain, Confusion, Dangerous Symptoms, Flashes of Light, Loss of Speech, Loss of Vision, Persistent High Fever, Severe Abdominal Pain, Shortness of Breath, Unexplained Changes in Bowel Habits, Unexplained Weight Loss

Question? I’ve been diagnosed with carpal tunnel syndrome.

Would regular hand and wrist exercises help me avoid surgery?
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Answer from Peter C. Amadio, M.D. - Probably not.

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When used alone, carpal tunnel exercises aren’t likely to relieve symptoms such as pain and numbness. And they don’t replace other carpal tunnel treatments, such as surgery, behavior modification or wrist splints.

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Carpal tunnel syndrome is caused by compression of the median nerve as it passes through the carpal tunnel and under the transverse carpal ligament at the wrist. A number of factors can contribute to carpal tunnel syndrome, including the anatomy of your wrist, certain underlying health problems and possibly patterns of hand use.

Nerve-gliding exercises — one type of carpal tunnel exercise — are meant to help the median nerve move normally, but they can sometimes worsen symptoms. If a median nerve remains trapped, nerve-gliding exercises can stretch, irritate or injure the nerve.

Despite their limits, carpal tunnel exercises may be helpful in some situations:

• To complement another treatment option. Carpal tunnel exercises may be helpful for mild to moderate symptoms when combined with other treatments, such as activity modification, wrist splinting or corticosteroid injections.
• After surgery to prevent the nerve from becoming scarred in the incision area. Range-of-motion exercises — which may include nerve-gliding exercises — can be helpful when there has been significant trauma to the area, such as a fracture that requires wrist surgery or repair near the carpal tunnel.

If your doctor recommends carpal tunnel exercises, start them gradually to ensure they don’t cause more harm than good.

Go to the Mayo Clinic web site for more information about carpal tunnel and other problems you may want to research.

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by Chris Lillis, MD

The tragic irony of pharmaceutical coupons

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As a primary care physician in private practice, I have my own little taste of celebrity.

Every day attractive people come to my office seeking time to speak with me and collect my autograph.  They fawn over my partners and I, and bring us food for lunch, and will invite us to the nicest restaurants in town for dinner.   These people also used to bring gifts, until they were barred from doing so a couple of years ago.  I must admit, they are not doctor-groupies.  They are pharmaceutical marketing representatives. Rather than stalking me, they are just performing the job they are paid to do.

Each year, the pharmaceutical industry and its army of salespeople spend billions of dollars marketing brand name patented drugs.  Annual estimates range from $20-60 Billion every year.    Sadly, this represents almost 30% of their sales revenue, while they invest about 11% on research and development of new pharmaceuticals.

Marketing practices of pharmaceutical companies should not be news, but you may not be noticing the building battle between insurers and pharmaceutical companies unless you are being “detailed” every day like me.

The formularies kept by private insurance companies are a great source of pain for pharmaceutical marketing professionals.  These are lists of available drugs, categorized into tiers. Tier 1 drugs are often generics: very inexpensive, and therefore offered to patients at very low copayments.  Tier 2 drugs are brand name drugs without generic alternatives, and at the other end of the spectrum are Tier 3 drugs – typically brand name drugs that may be new to market, and have several alternatives both generic and brand name. As you advance up the tiers, the copayments rise.  In order to force more generic medication usage, insurance companies are rapidly increasing these copayments to reduce their expenditures.

So begins the battle.  Pharmaceutical companies know that high copayments are effective ways to encourage patients to ask their doctors to prescribe generic drugs.  So pharma lobbies the insurance companies to reduce the tier status of their drugs.  In some cases, this leads to drugs being switched tiers, sometimes quite often.  A tier 3 drug that gets bumped down to tier 2 becomes a marketing highlight.  And it always leaves those of us with prescription pads guessing and rather frustrated.

The latest trend I have observed: coupons.  Pharmaceutical representatives will provide physicians coupons to give to patients for their new product.  The most generous of these coupons will actually cover the entire copayment of the drug, thereby eliminating the incentive designed by the insurance industry to encourage generic drug use.

Coupons may be great for individuals with higher copayments set by their insurers, but they do nothing to lower our national health care expenditures.  In fact, coupons encourage higher costs for pharmaceuticals.

The tragic irony of the coupon scheme devised by pharmaceutical marketing is that Medicare Part D patients cannot use them. The government by regulation prohibits any inducement that would directly or indirectly cause the government to spend money. Hence these coupons are not permitted to be split billed with Medicare or Medicaid.  Those who need help to defray their prescription costs the most cannot use them, but in some way I am glad.  This forces me to choose generic prescriptions more often.

The pharmaceutical industry lobbyists have been successful thus far in avoiding regulations that would hurt their profits.  But this is leading to skyrocketing costs.  In both the inception of Medicare Part D and in the passage of the Affordable Care Act, Congress neglected to provide the authority to Medicare to negotiate the prices of prescription medicines, leaving it to the private insurers who administer Medicare Part D.  This has led to greater profits for pharma at the direct expense of the consumer and taxpayer.

A study conducted by a prominent health care economist, funded by the Robert Wood Johnson Foundation, found that if Medicare adopted the Veterans Affairs (VA) drug formulary, America would save $14 billion a year on drug costs.  The VA directly negotiates drug costs with manufacturers, and its evidence-based formulary is able to keep drug costs down.

If any politician were bold enough to advance the proposal of allowing Medicare to negotiate drug prices, I can imagine the demagogue’s argument: “Don’t allow government to restrict your choices of drugs!”  Except that the facts point to health care consumers much preferring to have lower drug costs than infinite choices of expensive brand name drugs.  Polls show 80% of Americans would choose generic medicines in order to save money.

Between pharmaceutical marketing costs and the inflated prices of brand name medicines, there are tens of billions of dollars to be saved in health care expenditures each year.  I am confident the pharmaceutical industry will fight for those billions with vigor, but will we?

Chris Lillis is an internal medicine physician who blogs at Progress Notes.

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by Shantanu Nundy, MD

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At 3am on Jan 1st 2010 my cousin-brother stubbed his last cigarette. New Year’s resolutions to quit smoking, lose weight, or change another bad habit are certainly not uncommon. Having tried — and failed — to quit a number of times before, my cousin took a bold, new approach to quitting.

Whether a cleverly devised plan, or just a whim, he decided to post his quitting on Facebook.

On January 4th, four days after smoking his last cigarette, he updated his status: “bring it on day 5!” Within hours, three people responded that they “Like” his comment; five others commented favorably with messages such as “Good for you!!!” and “Keep it going, bro.”

Encouraged by the support he received, my cousin posted another update three days later. Using his iPhone he wrote that he ”is one week non-smoking!!!” Again, within hours, eight people responded that they liked his comment and another two offered congratulatory remarks.

Though he didn’t necessarily realize it at the time, my cousin was creating a community of supporters through Facebook. The scientific literature is filled with evidence on the value of peer support for behavior modification. The “T” in the START mnemonic for quitting endorsed by www.smokefree.gov is to “Tell family, friends, and coworkers that you plan to quit.” This recommendation is based on the notion that smoking is not purely a chemical addiction; it has important environmental, social, and cultural elements, too.

Our peers do not only provide support for quitting on good days; they are equally invaluable on bad days. Three days after his last post, my cousin started feeling lousy. He posted having “a crazy head cold. Never felt this crappy in several years.” While he may have had caught a cold, it is more likely that he was going through nicotine withdrawal. Was this a simple update or a call for help? Seven of his friends responded offering home remedies and supportive messages. The next day he was feeling better and posted, “Twelfth smoke free day!,” garnering nine “Like”’s and seven enthusiastic comments. He responded, “Thanks for all the support everyone. Really helps me to stay on the path.”

People who quit often benefit from the support of a physician and other health care providers. Whether it be in the form of counseling, pharmacologic support, or referrals studies show that people who quit with the support of a health care provider have a much higher chance of success.

The problem is that assistance is often needed in real-time. I once shadowed a tobacco cessation counselor at my hospital who offered his cell phone number to every patient he saw, but this kind of dedication is rare. My cousin’s next post read, ”19th smoke-free day in a row. Maybe enjoy a cigar on the 30th day…let me ask my doctor…?” Here, too, surprisingly Facebook offered a solution. I immediately responded applauding him for his progress but also gently suggesting that it was probably too early for a celebratory puff.

Real-time support is critical because the decision to quit smoking isn’t made once. It’s made every day – in fact multiple times a day – whenever the nicotine craving hits. This is a major reason why social networks are so critical. Week 3 he posted that he ”… is wondering why day 21 is harder than 3,4,5 and 6 combined.” While my cousin could have called up 10 of his friends and told them that he was having a difficult time that day, it was clearly easier and perhaps more effective to post about it instead. After seeing his post, I called him to get his mind off of smoking.

Research in smoking cessation and behavior modification has demonstrated the importance of social networks. In recent years, there has been fascinating research showing, for example, that overweight people are more likely to have overweight friends and that happiness is contagious. The challenge in modern day society is how to activate these social networks to affect good.

Previous generations made greater use of formal networks such as religious gatherings, town hall meetings, and social clubs. While these avenues are still important today, increasingly technology is playing a role in defining our communities. While e-networks are less personal, this is not necessarily always a bad thing, especially when it comes to changing bad habits. They also benefit from a wider reach, being more real-time, and increasingly more dynamic.

Whether by design or accident, my cousin stumbled on an innovative approach to leverage social networks to quit smoking. And quitting smoking is just one application of e-social networks. Imagine the analogy for weight loss: “I lost 2 lbs this week!” soliciting responses of “Way to go!”, and “Feeling too lazy to go to the gym” being met with “You can do it! The hardest part is getting there!!”

Finally, though it is not as readily apparent, my cousin is not the only one benefiting from his Facebook posts. The positive effects of social networks go both ways. Friends following his posts are no doubt taking note of his success and being motivated to better themselves. His last post reads: “Still at it 41 days now. Feeling great and about to start a kick ass work out regimen.” Who knows? If he starts posting about his work outs on Facebook, I may just go to the gym more often.

Shantanu Nundy is an internal medicine physician who blogs at BeyondApples.org.

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Technorati Tags: Facebook, Quit Smoking, smoking

By Kristina Fiore, Staff Writer, MedPage Today . The FDA has approved a short-acting opioid painkiller with abuse-deterrent properties, the drugmaker Pfizer announced Monday. Oxecta, a new formulation of oxycodone, had previously been under development as Acurox, which included niacin to deter oral abuse. That version received a thumbs down from an FDA advisory panel in 2009. The new drug uses “Aversion” technology, licensed from Acura Pharmaceuticals — which is described as a “unique composition of commonly used pharmaceutical ingredients” — to stop potential abusers from crushing, chewing, snorting, or injecting the opioid. It does not deter oral abuse. But Pfizer noted in a statement that the potential to abuse the drug via these routes still exists and “there is no evidence that Oxecta has a reduced abuse liability compared to immediate-release oxycodone.” In an earlier interview, Gail Cawkwell, MD, vice president of medical affairs at Pfizer, told MedPage Today that the technology causes the drug to break down into crumbled chunks instead of powder if crushed, and turns it “sudsy” if it is mixed with liquid and drawn into a syringe. Oxecta is indicated for acute and chronic moderate-to-severe pain and is contraindicated in patients with respiratory depression, paralytic ileus, bronchial asthma or hypercarbia, and in those with a hypersensitivity to the opioid. Among the most common adverse reactions are nausea, constipation, vomiting, headache, itchiness, trouble sleeping, and dizziness, according to Pfizer. The new formulation joins a handful of other abuse-deterrent opioids that are on the market or in development. Purdue Pharmaceuticals, maker of long-acting oxycodone (OxyContin), had a tamper-proof version of its drug approved last year. Making drugs harder to abuse has been one key strategy for some companies in an attempt to control what the government has deemed an epidemic of prescription painkiller abuse. Pfizer acquired Oxecta when it merged with King Pharmaceuticals last year, along with an abuse-deterrent formulation of long-acting oxycodone (Remoxy) which is up for FDA approval on June 23.

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by Mike Cadogan, MB ChB

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Crossing multiple time zones can produce a constellation of symptoms known as jet lag.

Jet lag is most noticeable in the first 24-48 hours following travel and can last for up to 5 days before individuals return to normal functioning. Symptoms are closely affected by both the length and direction of travel. Symptoms include: reduced alertness, night-time insomnia, loss of appetite, depressed mood, poor psychomotor coordination and reduced cognitive skills. Work capacity and peak power are also reduced.

Factors affecting poor recovery from travel include

• A lack of sleep or very restless sleep during flight
• Dehydration from dry environment of the aeroplane cabin (contribute to tachycardia and headaches)
• Number of time zones crossed
• Direction of travel (westward travel is easier to tolerate than eastward)
• Fitness levels (fitter people adapt better after travel)
• Personality (outgoing types appear to adjust quicker)

One of the major challenges of travelling with elite athletes is to minimise the negative symptoms associated with international travel in as natural a way as possible. To best refine a travel management plan it is first prudent to understand the pathophysiology of the sleep/wake cycle.

Daily circadian variation exists in elite athletes with peak performance occurring in the afternoon and early evening with improved flexibility, reaction time, strength and mood at this time of day. International travel disturbs these circadian rhythms and can have a negative impact on performance.

Click to enlarge

Melatonin

Synthesis of melatonin by the pineal gland is inhibited by light and stimulated by darkness.

Melatonin has been dubbed the “hormone of darkness.” Secretion of melatonin commences each evening as the Dim-Light Melatonin Onset (DLMO), peaks in the middle of the night, and gradually falls during the second half of the night, with normal variations in timing according to an individual’s chronotype.

Increases in the level of melatonin causes the body to feel less alert and has an important role in inducing sleep and producing the symptoms of jet lag.

Dysregulation of melatonin secretion and circadian rhythm disturbances are thought to be the common links which underlie jet lag and affective mood disorders. As a result of its regulatory effects on the circadian system, it follows that melatonin may be used effectively to treat the range of symptoms that accompany transmeridian air travel.

Melatonin acts on MT(1) and MT(2) melatonin receptors located in the hypothalamic suprachiasmatic nuclei, the site of the body’s master circadian clock. Melatonin can reset disturbed circadian rhythms and promote sleep in jet lag and other circadian rhythm sleep disorders, including delayed sleep phase syndrome and shift-work disorder. Post-flight melatonin administration works efficiently in transmeridian flights across less than 7-8 times zones.

Pharmacological implications

Despite pathophysiological evidence, there is still a persisting culture of players requesting stronger sedative agents to assist in artificially creating a new time-zone sleep/wake cycle. Agents such as bezodiazepine (diazepam) and non-benzodiazepine hypnotics such as Zolpidem are still frequently prescribed to travelling elite athletes to reduce the negative symptoms of jet lag.

I am currently implementing a more evidence based approach to the management of circadian cycle disruption by administering melatonin or the newer melatonin receptor agonists. On this South African tour we are trialling the use of direct sunlight exposure for 30 minutes each morning (in addition to daily excersise regimes) and the administration of 2-4 mg doses of melatonin at normal bedtime in the setting of darkness (22:00 local time). So far the administration of melatonin has had a fantastic effect in organing an effective sleep/wake cycle for the players and has drastically reduced the administration of previously abused agents.

Ramelteon and agomelatine are melatonin receptor agonists which, compared to melatonin itself, have a longer half-life and greater affinity for melatonin receptors and consequently are thought to hold promise for treating a variety of circadian disruptions. We will trial these agents for the next international tour.

Mike Cadogan is a physician in Australia who blogs at Life in the Fast Lane.

Technorati Tags: Jet Lag, Melatonin

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by dr_som, MD

I love to pick up my two year old from daycare. Her language is becoming increasingly complex with small sentences, lots of gesturing and expression. When I ask how school was, she says, “Miss you. I crying.” Or, “I running fast with friends.” Or sometimes a confident, “good,” with a head nod.

Yesterday, she said, “friend, bite me.”

Her very kind teacher confirmed the event, and asked my daughter to show me the mark. No broken skin. No big deal. I reassured the teacher. I signed the incident form.

My daughter told me, “Miss Jean hold me and wash it. Tommy time out.”

I continue to marvel at the calm and skill of good daycare teachers. Miss Jean provided the proper hygiene, comfort, and discipline without yelling or blaming. I did not even ask what lead up to the incident because it did not matter. Asking my daughter why Tommy bit her would serve no purpose. Biting is never justified, and how can she speculate about what he was thinking.

I wanted her to learn forgiveness. I said, “You bite mommy and daddy sometimes. I bet he said sorry. You are OK. He’ll use his words next time.”  She nodded yes.

When infants mouth objects, we think nothing of it. Parents know it is normal for children to put things in their mouths. Most children start this oral behavior around 4 months of age and stop anywhere from 9 to 18 months with the behavior becoming less frequent as they learn more about the world through other methods. Biting other children or adults begins when chewing on other objects slows. Around this same time children are increasingly aware of social behaviors and are both curious and a little anxious about interacting with other people.

Biting is very natural and all children around the age of 12 months begin to experiment with biting Mom or Dad. Then they might try biting siblings or friends. The behavior peaks around 24 months and then declines. Three year old children rarely bite because they have gained social competence and the language skills to mediate frustration.

Please know that all children bite. No matter how you handle the behavior, your child will outgrow it by three years old. How you react may affect how quickly the behavior stops.

To nip it in the bud

• A simple, “biting hurts” will do. Nobody should be called bad. No shouting.
• Give affection and attention to the child that was bitten.
• Briefly ignore the biter. Time out may not be necessary as ignoring the child sends a clear message that biting is an antisocial behavior.
• Let the biter say sorry or hug the person he has hurt.
• Anticipate biting and offer distraction or offer words that the child can use instead.
• If the skin is broken, see your doctor about the need for antibiotics or a tetanus shot. Usually soap, lots of water, and maybe a cool compress are all you need.
• Choose a daycare with good staffing ratios, at least one adult to four children for toddlers. A quality provider engages the children, minimizes boredom, recognizes fatigue and understands that biting happens.

Biting is almost never a sign of abnormal development in an otherwise normal child. My autistic child never bit anyone, but my five year old used to and my two year old still does.

Biting is a sign of normal social experimentation. I just hope I can keep that in mind when my daughter comes home with her first hickey.

“dr_som” is a pediatrician who blogs at Pensive Pediatrician.

Technorati Tags: Biting, Parenting

By Fran Lowry

NEW YORK (Reuters Health)  - Infants and children being treated with narcotics routinely receive overdose amounts, according to a study presented in Denver this past weekend at the annual meeting of the Pediatric Academic Societies (PAS).

Narcotics are usually given to young children in liquid formulations, which are difficult for parents to measure correctly. Also, pharmacists may not account for the child’s weight when prescribing, said Dr. William T. Basco, Jr, from the Medical University of South Carolina in Charleston.

“Narcotics involve a large proportion of drugs that are most commonly involved in adverse drug events and we also know that parents have problems properly measuring liquid preparations, so taking those two factors together, we wanted to find out more about the frequency of potential overdoses in young children,” Dr. Basco told Reuters Health.

He and his colleagues identified the top 19 narcotic-containing drugs prescribed for children aged 0-36 months from a review of 2000-2006 South Carolina outpatient Medicaid data. They calculated the expected daily dose of the narcotic based on Centers for Disease Control and Prevention growth chart data to impute the weight of each child as the 97th percentile based on age and gender, and then compared that dose with the actual amount of narcotic dispensed by the pharmacy.

During that time, there were 149,791 prescriptions for narcotic-containing preparations, for patients with a mean age of 18 months.

“Most of these prescriptions were appropriate, for post-operative or post-trauma pain. Some were for antitussants, and I think that is an important point to emphasize,” Dr. Basco said.

Fifteen percent of the prescriptions contained an overdose quantity of narcotic, the research team found. The average excess amount of narcotic dispensed was 53% more than expected.

The researchers also found that the younger the children, the more frequent the overdoses. More than half (61%) of infants aged 0 to 2 months who received a narcotic got an overdose, compared with 35% of infants 3 to 5 months old, 17% of infants 6 to 11 months old, and 8% of children 12 months or older (p<0.0001).

Younger children also got larger overdoses. Compared to expected doses, actual doses were 90% higher in the 0 to 2 month age group, 53% higher in the 3 to 5 month group, 36% higher in the 6 to 11 month set, and 34% higher for babies 2 months and older (p<0.05).

In addition, the youngest infants were dispensed more than twice the expected quantity 20% of the time. In comparison, infants 3 to 5 months got more than twice the expected quantity 3.8% of the time, infants 6 to 11 months, 1.5% of the time, and for children 12 months or older, it was just 0.2% of the time (p < 0.05).

“Clinicians need to remember that the younger the child, even small deviations from the appropriate dose will make a big difference,” said Dr. Basco. “Giving 20% more drug when you are 5, 6, or 10 years old doesn’t matter as much, but when you are a 2-month-old, then it matters a lot.”

The sedative effects of the narcotics can cause young children to stop eating and drinking and become dehydrated. “Very few would die from overdose but that is possible, but the greater issue is dehydration and this is harmful,” Dr. Basco said.

He added that, ideally, all pediatric prescriptions should be based on the child’s weight.

“For inpatients, our hospital pharmacy will not send any drugs to the floor unless the child’s weight is on the order, but ambulatory prescriptions that you get at Walgreens or CVS do not consider the child’s weight,” Dr. Basco added.

Click here to read the rest of this article.

Technorati Tags: Children, Drug Overdose, Infant, Medicine, Narcotic, Overdose