We Need To Reduce Antibiotic Use And Misuse

Today's post from huffingtonpost.com (see link below) looks at antibiotics and explains why we've got to control their over-prescription, both because of growing resistance, the difficulty in developing new ones, and (in our case) the effect some of them can have on our nervous systems. There is no direct reference to neuropathy but it's a very important topic and certainly relevant to neuropathy sufferers if you look at the damages fluoroquinolone antibiotics can do to your nervous system (see more articles here on the blog). Worth a read.

Stop Killing the Good Guys! Protect Your Child's Microbiome From Antibiotic Overuse
Aviva Romm Practicing Family Physician, Midwife, Herbalist Posted: 01/08/2015

There's no doubt that antibiotics are a good thing. They save lives every day. We can, in part, attribute our longer lifespans, reduction in infant mortality and childhood deaths from life-threatening infections, and the near elimination of childbirth-related maternal deaths from infections in hospitals to antibiotics. As a medical doctor I am grateful to be able to prescribe them for serious bacterial and other appropriate infections, for example Lyme disease. As with many things, however, more is not always better. And this is certainly the case with antibiotics.

The average child in the United States will receive between and 10 and 20 courses of antibiotics by the time he or she is 18 years old. (2) We are so accustomed to antibiotics being prescribed for childhood illnesses that we assume that they are as safe as they are common. But this is far from the truth. We are now learning the hard way that the common overuse of antibiotics, both as medicines and in our foods (they are given to cattle and poultry to keep them "healthy" until they are slaughtered for food; antibiotics also promote growth in these animals by the same mechanisms that their chronic use increases the risk of obesity in humans) is responsible for two major health problems: global antibiotic resistance to serious infections, and damage to the human microbiome.

This growing awareness that antibiotic overuse is dangerous for both public and personal health requires us to drastically and immediately rethink and adjust our antibiotic use. In doing so we can prevent our children from developing life-long chronic illnesses associated with microbiome damage, some of which rival the seriousness of the bacterial infections that used to threaten them, and we can reduce the major global threat of antibiotic resistance we all face.

Antibiotics, Your Child's Microbiome, and Chronic Disease

Antibiotics kill bacteria. The problem is that they not only kill off the bad guys (and as you'll see below, because of antibiotic resistance, they are doing this less effectively!); they kill off the good ones, too. When we give antibiotics to children at a young age or frequently enough, some of the good guys may never fully recover. These good gut flora, and their composite, our microbiome, are essential for more functions that protect and support our health than we'd ever imagined until recently. We now know that microbiome damage directly and significantly increases the risks of our children developing long-term health problems including: food, environmental, and seasonal allergies, eczema, asthma, ulcerative colitis, Crohn's disease, obesity (even when they're not over-eating), diabetes, and cardiovascular disease. (1) (4)

Antibiotics are given to between 30 and 50 percent of all women during pregnancy or labor. (2) Mom's exposure to antibiotics perinatally also negatively affects the breast milk microbiome, which is part of what is supposed to help colonize baby's gut with beneficial flora. (5) Additionally, 34 percent of babies in the U.S. are born by cesarean. These babies miss out on the important inoculation their gut flora is meant to receive through natural exposure to mom's vaginal flora, thus compounding the problem. Our babies thus begin their antibiotic exposure even before birth, and as a result damage to their formative microbial populations begins before they've had a chance to establish their optimal gut flora. If your baby was born by cesarean section, or if you did need to have antibiotics in labor, no need to be worried! Start your baby on a probiotic in the day or so after birth. Data has shown that while we can't necessary restore the native flora baby might have had, we can prevent eczema, allergies, and asthma with early probiotic treatment. (6)

By age 24 months, 69 percent of children in the U.S. have received at least one systemic antibiotic course, though the average is 2.3 courses for ear infections, bronchitis, sore throat, and other common childhood illnesses. Yet according to the Centers for Disease Control, and other official reports, at least 50 percent and as many as 70 percent of the antibiotics prescribed for children for these and other symptoms/conditions are unnecessary and inappropriate. (3)

Reactions to antibiotics are responsible for at least 140,000 hospital visits annually in the US. (3) One in every five emergency department visits due to a medication reaction is due to antibiotics, and in kids under 18 years old they are the most common cause of drug reactions. When a child takes an antibiotic that is not needed, not only is she or he getting no benefit; she or he is exposed to all the risks of harm and the use of that medication adds to antibiotic resistance.Why are antibiotics overprescribed? There are four main reasons:
Doctors think that parents expect an antibiotic prescription when they bring their child in for a sick visit -- and many do -- leading to 50 to 70 percent of the antibiotics that are prescribed. (4)
Doctors are afraid to get sued should an infection that they didn't treat with an antibiotic turn out to be more serious than anticipated.
Doctors don't feel that they have time to explain the problems with antibiotics to parents in the time allocated for a child's sick visit, whereas it is quick and easy to prescribe an antibiotic.
Doctors aren't knowledgeable about alternatives to antibiotics and want to prescribe something they think will help.

The Centers for Disease Control and Prevention (CDC) has been on a several decade-long campaign to get physicians to reduce their antibiotic overprescribing. While there has been about a 20 percent decrease in antibiotic prescribing over the past 20 years as a result, the rates of overprescribing remain shockingly high, according to the CDC and other researchers. (3)

Antibiotic Resistance: A Global Health Threat

We are in the midst of a global health crisis -- antibiotic resistance, which is a direct result over the overprescribing and inappropriate prescribing of antibiotics, and the overuse of antibiotics in the meat industry.

Antibiotic resistance is not something that develops just in the individual -- that is, it's not just that you become resistant to that antibiotic -- it means that the bacteria themselves have learned to outwit the antibiotic so that the antibiotic is no longer effective in treating anyone who is infected with the resistant strain.

Each year in the U.S. alone over 2 million Americans acquire serious infections with bacteria that are now resistant to some or all of the antibiotics that we have to treat those organisms, and at least 23,000 people die each year as a result of antibiotic resistance. (3) Global leaders in public health have declared that these "nightmare bacteria" pose a catastrophic threat to every person in the world!

Five Steps to Preventing Antibiotic Overuse In Your Child
 
Promote health in your children: Preventing recurrent upper respiratory infections including coughs, colds, sore throats is an important and logical step you can take to prevent antibiotic overuse. Less need for them = less use of them! A healthy diet of natural foods with plenty of good quality protein, good quality fats, plenty of fresh vegetables, and low sugar, reduction of chronic stress, playing outside and getting dirty to get exposure to natural probiotics in the soil, and regular hand-washing with soap and water (don't use antibacterial soaps -- these also contribute to antibiotic resistance), along with a multivitamin that contains adequate iron, vitamin D, essential fats, and zinc, all support optimal immunity. The gut can also be nourished and the microflora supported with a probiotic.
Choose organic for your meats and dairy: While it may not be feasible for you to serve your family an entirely organic diet for economic reasons, at least use only antibiotic-free meats and poultry, and organic dairy. These are where the heavy antibiotic exposures come from in the diet -- so it's where you can make your money count most toward reducing antibiotic exposures.
Know your options -- Get Smart: The CDC has a website called Get Smart that is dedicated to preventing antibiotic resistance through preventing antibiotic overuse. You can find information on the primary infections for which antibiotics are overused, how to know when your child really does need an antibiotic, and how to avoid unnecessary use. Included is also information on comfort measures and medical alternatives for common symptoms ranging from cough and sore throat, to fever and ear infections. I don't necessarily agree with all of the CDC's alternative treatment recommendations, particularly the liberal use of Tylenol and ibuprofen, which have their own potentially serious side effects, but the overall information is very useful and also provides solid information to bring to your child's doctor's appointment to share with the pediatrician in case there is disagreement over whether the antibiotic is necessary and appropriate.
Know your rights: Doctors are not infallible nor are we omniscient. And not all doctors are aware of the importance of avoiding antibiotic overprescribing, so some may may insist on the prescription in spite of the CDC's guidelines. If you cannot reach agreement with your pediatrician, you have the right to seek another opinion or to change doctors. You should not be coerced into giving unnecessary antibiotics to your child. If your pediatrician is, however, insistent, find out why -- she may have a different perspective on your child's symptoms and of course the CDC guidelines are just that -- clinical judgment is also important.
Use natural treatments for the symptoms of common childhood illnesses whenever possible.

References
1. Bailey LC et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr 2014 Sep 29
2. Blaser, M. Stop the killing of beneficial bacteria. Nature. Vol 476, 393-94. Aug. 2011.
3. CDC. Antibiotic Resistance Threats in the United States, 2013. US Dept of Health and Human Services, Centers for Disease Control and Prevention.
4. Dooling KL et al. Overprescribing and inappropriate antibiotic selection for children with pharyngitis in the United States, 1997-2010. JAMA Pediatr 2014 Sep 29
5. Williams, F. (2013). Breasts: A natural and unnatural history. New York: W.W. Norton.
6. Osborn DA, Sinn JK. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst Rev. 2007;17: CD006475.

Aviva Romm, M.D. is a Yale-trained, Board Certified Family Physician, midwife, and herbalist helping extraordinary women live their best lives through optimal health. An award-winning author and the leading international authority on botanical, integrative and functional medicine for women and children, she combines her unique backgrounds to guide women in transforming their health -- and their lives. She is also a leader in the revolution to shift the current medical system into one that respects the healing capacities of the body and nature. Dr. Romm has bridged her interests in traditional medicine with her knowledge of science for over 30 years, specializing in the impact of stress, food and lifestyle on food cravings, weight, immunity, hormone imbalances, and women's chronic health concerns. She also provides comprehensive guidance on natural fertility, pregnancy, and birth, and pediatrics. Dr. Romm practices Functional Medicine for Women and Children at The UltraWellness Center with Dr. Mark Hyman in Lenox, MA. Visit her website www.avivaromm.com for free access to her e-book, Herbal Medicines for Kids: Taking Charge of Your Child's Health... Naturally.

http://www.huffingtonpost.com/aviva-romm/stop-killing-the-good-guy_b_6396546.html?utm_hp_ref=healthy-living

Why Do We Take Extra Vitamin B For Neuropathy

Today's post from onlinelibrary.wiley.com (see link below) is an important one for several reasons, not least of which is how it shows readers how complex medical studies are set up and planned. It also questions the role of Vitamin B (in all its forms) in neuropathy treatment. It is true, wherever you look on the internet, you will see articles blithely recommending vitamin B supplementation as an answer to neuropathy symptoms and this has resulted in patients rushing to health food shops and supermarkets to stock up on vitamin B supplements. The problem is that serious studies into vitamin B supplementation are conspicuous by their absence, although occasionally, you'll see a vague warning not to 'overdose'. The most important lesson from all this is that you should only ever supplement an existing deficiency and how will you know you're deficient in vitamin B unless your doctor tests you for it? 90% of the time, patients look at the disease and wrongly conclude that extra vitamin B is the answer, without finding out the levels in their own bodies. Apart from this; which sort of vitamin B are you going to choose...and why. You'll often see vitamin B12 being recommended; or Bi, B2 etc etc, or combinations of B compounds. You get the picture!
This article refers to a study begun in the middle of last year intended 'to assess the effectiveness and safety of vitamin B supplements for the management of pain and nerve damage in people with diabetic peripheral neuropathy.' It also examines the various sorts of vitamin B and explains their purpose. Pretty important don't you think and hopefully it's just the first of many serious studies into supplements and nerve damage. The problem is that when people exhaust all the standard chemical options and the symptoms continue, their next port of call is the supplement industry and its all too voracious marketing campaigns. There's nothing wrong with that, as long as you do your research first and consult your doctor and then stop the supplement if it's having no effect!! Otherwise you're sticking a pin in the ever-growing supplement list and hoping for the best...never the healthiest option...I'm sure you agree.

Vitamin B for treating diabetic peripheral neuropathy
Hanan Khalil, Helen Chambers, Vivian Khalil, Cynthia D Ang

First published: 8 June 2016
Editorial Group: Cochrane Neuromuscular Group
DOI: 10.1002/14651858.CD012237View/save citation
Cited by: 0 articles

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effectiveness and safety of vitamin B supplements for the management of pain and nerve damage in people with diabetic peripheral neuropathy.

Background
Description of the condition

Peripheral neuropathy is the most common risk factor for foot ulcers in people with diabetes (Duby 2004). More than 80% of all non-traumatic amputations in diabetic patients are the result of foot ulcers (Singh 2005). In 2010, the estimated world prevalence of diabetes was 285 million, a figure expected to rise to 439 million by 2030 (Shaw 2010). Diabetic peripheral neuropathy (DPN) is then expected to affect around 236 million, constituting a major cause of mortality and morbidity, with a significant associated financial cost (Tesfaye 2012). The annual cost of DPN in the United States was estimated to be USD 10.9 billion in 2010 (Gordois 2003; Zhang 2010).

Diabetic neuropathy can be divided into four broad patterns, depending upon which nerves are affected: DPN, proximal neuropathy, autonomic neuropathy, and focal neuropathies (American Diabetes Association 2014; Boulton 2004). Diabetic neuropathy affects long fibres first, including the feet and distal legs. Proximal neuropathy is often asymmetric and may involve the thighs, hips, or buttocks. Autonomic neuropathy can cause dysfunction of the gastrointestinal system, blood vessels, and urinary system, and sexual dysfunction. Focal neuropathies often occur at common sites of nerve compression and affect nerves such as the ulnar and median nerves in the arm, the peroneal nerve in the leg, nerves of the thoracic and lumbar regions, and specific cranial nerves (Boulton 2004).

The American Diabetes Association has defined DPN as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” (American Diabetes Association 2014). Symptoms of DPN include numbness or reduced ability to feel pain, muscle weakness, difficulty walking, and serious foot problems (Boulton 1998; Hughes 2002; Huskisson 1974).

No gold standard for diagnosing DPN exists; the history and physical examination are key, as the diagnosis remains clinical (American Diabetes Association 2014). Supportive semi-quantitative testing, such as monofilament testing (using von Frey hairs), nerve conduction studies, electromyography, and quantitative sensory testing, can also be used (Bril 2013). Exclusion of non-diabetic causes should also be undertaken, again through history, examination, and the judicious use of investigations such as serum vitamin B₁₂, thyroid function tests, blood urea nitrogen, and serum creatinine (Perkins 2001).

Early diagnosis and management of DPN are crucial for the prevention of amputations, foot ulcers, and other injuries. Successful diagnosis and management require early screening for high-risk individuals (American Diabetes Association 2014; Khalil 2013a).

Treatment of DPN is multifaceted: components include stable glucose control; regular physical check-ups including foot care; patient education; and specialist care when needed (Callaghan 2012). Pain management includes the use of medications such as, for example, pregabalin, sodium valproate, dextromethorphan, tramadol, opioids and, in some cases, topical capsaicin and lidocaine (Khalil 2013b).

Description of the intervention

The B vitamins comprise eight water-soluble compounds that have essential roles in cell metabolism: vitamin B₁ (thiamine), vitamin B₂ (riboflavin), vitamin B₃ (niacin, niacinamide, or nicotinic acid), vitamin B₅ (pantothenic acid), vitamin B₆ (pyridoxine, pyridoxal, pyridoxamine, or pyridoxine hydrochloride), vitamin B₇ (biotin), vitamin B₉ (folic acid) and vitamin B₁₂ (hydroxycobalamins, cobalamins). Each one of these components has a different physical and chemical structure and completes an essential function in the human body (Chaney 1992; Olson 1996).

Vitamins B₁, B₂, B₃, and biotin are involved in energy production; vitamin B₆ is required for amino acid metabolism. Thiamine is converted to thiamine pyrophosphate which has a role in carbohydrate metabolism. Thiamine pyrophosphate also plays a role in the transmission of nerve impulses. Riboflavin is converted into flavin mononucleotide and flavin adenine dinucleotide that serve as coenzymes for respiratory flavoproteins. The active forms of nicotinic acid are coenzymes for proteins that catalyse oxidation-reduction reactions in tissue respiration (Chaney 1992; van Boxtel 2001).

Vitamin B₆ is converted to pyridoxal phosphate and is involved in the metabolic transformations of amino acids and in the metabolism of sulphur-containing and hydroxyl-amino acids. Pyridoxal phosphate is required for the synthesis of sphingolipids for myelin formation. Vitamin B₁₂ has several congeners: cyanocobalamin, hydroxocobalamin, methylcobalamin, and 5’-deoxyadenosylcobalamin. Vitamin B₁₂ and folic acid facilitate essential steps in cell division (Chaney 1992; Hillman 1996).

Common vitamin B deficiency features include peripheral neuropathy, depression, mental confusion, lack of motor co-ordination, and malaise. Vitamin B deficiencies cause various diseases in humans such as beriberi (thiamine deficiency), pellagra (nicotinamide deficiency), megaloblastic anaemia (folic acid deficiency), and pernicious anaemia (cobalamin deficiency) (De-Regil 2010; Lassi 2013; Rodríguez-Martín 2001). The therapeutic doses for the various forms of vitamin B complex range widely, from 3 μg/day for vitamin B₁₂ to 18 mg/day for vitamin B₃ in adult males (Chaney 1992; Hillman 1996).

How the intervention might work

The mechanisms by which neuropathic pain develops in diabetes are unclear; mechanisms postulated include alteration in peripheral blood flow, increased vascularity, oxidative stress, and autonomic dysfunction (Edwards 2008; Tesfaye 2011). Overall, there is a paucity of evidence on the role of B vitamins in diabetes. Several studies found lower than normal levels of thiamine in people with diabetes, thought to be due to high renal clearance of thiamine and increased albuminuria in diabetes (Thornalley 2005). Moreover, vitamin B₁₂ deficiency has also been observed in patients with diabetes, partially explained by metformin-induced vitamin B₁₂ deficiency, particularly among people on high doses of metformin (Kibirige 2013). Mecobalamin is a derivative of vitamin B₁₂ involved in processes essential to myelin repair (Sun 2005).

Why it is important to do this review

Untreated DPN is not only associated with a significant cost to the health care system, but has a serious impact on a person's quality of life and general health. If left untreated, serious complications such as loss of function and amputations can occur. To date, evidence on the effectiveness and safety of vitamin B supplements for the treatment of DPN as an additional or alternative option to current treatments have not been fully evaluated. This review will address these issues (Rolim 2009).

Objectives

To assess the effectiveness and safety of vitamin B supplements for the management of pain and nerve damage in people with diabetic peripheral neuropathy.
Methods
Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) and quasi-RCTs (studies that allocate participants to groups by methods that are partially systematic, for example by allocation, case record number or date of birth). We will apply no language limitations. We will include studies completed but not fully reported to reduce the risk of publication bias.

Types of participants

We will include trials of adults, children, or both, with a diagnosis of DPN based on symptoms, abnormal physiological test results, or both. For the purpose of this review, we will use the definitions of diabetes and DPN set by the American Diabetes Association (American Diabetes Association 2014). We will exclude participants with other types of neuropathy. We will exclude people who are vitamin B depleted and taking supplements for replenishment. Participants should not have taken B vitamins in the six months before the start of treatment.

Types of interventions

We will consider trials for inclusion where the intervention is any dose and type of vitamin B supplement (thiamine (B₁), riboflavin (B₂), nicotinic acid (B₃), pyridoxine (B₆), and methylcobalamin, cyanocobalamin, hydroxycobalamin, methylcobalamin, or 5’-deoxyadenosylcobalamin (B₁₂), given by any route, singly or in combination as vitamin B complexes, in comparison to placebo, no treatment, or any comparators for a minimum period of 12 weeks. We will consider trials of vitamin B complexes so long as details of the components are provided.

We will exclude studies using supplements in combination with other vitamins or drugs unless the other vitamins or drugs are administered at the same dose in both intervention and control groups.
Types of outcome measures

Primary outcomes

For painful neuropathy: short-term (three months or less) change in pain intensity, measured as the number of participants with more than a 30% improvement in pain intensity.

For non-painful neuropathy: short-term change in impairment measured by a validated scale, e.g. neuropathy impairment score (NIS) (Dyck 2005).

Secondary outcomes

Long-term (after more than three months) change in pain intensity, measured as the number of participants with more than a 30% improvement in pain.

Long-term (after more than three months) change in impairment measured by a validated scale as for the primary outcome.

3. Change in quality of life measured by a validated scale (e.g. Short-Form 36 Health Survey (SF-36)).

4. Adverse events, reported as all adverse events, adverse events which led to cessation of treatment, and serious adverse events which were life-threatening, fatal, or required or prolonged hospitalisation.
Search methods for identification of studies

Electronic searches

We will identify trials from the Cochrane Neuromuscular Specialized Register, which is maintained by the Information Specialist for the Group. The Information Specialist will search the Cochrane Central Register of Controlled Trials (CENTRAL) (current issue in The Cochrane Library), MEDLINE (January 1966 to current), EMBASE (January 1980 to current), and CINAHL Plus (January 1937 to current). We will adapt the draft MEDLINE strategy in Appendix 1 to search the other databases.

We will also search the US National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/). We will search all databases from inception to present.

Searching other resources

We will search reference lists of all primary studies and review articles to identify additional references. We will search relevant manufacturers' websites for trial information. We will search for errata or retractions of included trials.
Data collection and analysis

Selection of studies

Three review authors (HK, CA, and VK) will independently screen titles and abstracts of references from the literature searches and code them as either 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full-text study reports or publications and three review authors (HK, CA and VK) will independently screen the full text and identify studies for inclusion. The review authors will identify and record reasons for exclusion of ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third person (HC). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table. The review authors will not assess trials in which they are investigators.

Data extraction and management

We will use a data extraction form, which has been piloted on at least one study in the review, for study characteristics and outcome data. Two review authors (VK and HK) will extract study characteristics from included studies.
 We will extract the following study characteristics.

Methods: study design, total duration of study, details of any 'run in' period, number of study centres and location, study setting, withdrawals, and date of study.

Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline characteristics, inclusion criteria, and exclusion criteria.

Interventions: intervention, comparison, concomitant medications, and excluded medications.

Outcomes: primary and secondary outcomes specified and collected, and time points reported.

Notes: funding for trial, and notable conflicts of interest of trial authors.

Two review authors (CA and HK) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if the trial report did not provide usable outcome data. We will resolve disagreements by consensus or by involving a third person (VK). One review author (HK) will transfer data into Review Manager (RevMan 2014). A second author will check the outcome data entries. A second review author (CA) will spot-check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies

Two review authors (HK and CA) will independently assess risk of bias in each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (VK). We will assess the risk of bias according to the following domains.

Random sequence generation.

Allocation concealment.

Blinding of participants and personnel.

Blinding of outcome assessment.

Incomplete outcome data.

Selective outcome reporting.

Other bias.

We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table. We will summarise the 'Risk of bias' judgments across the included studies for each of the domains listed. We will consider blinding separately for different key outcomes (e.g. for unblinded outcome assessment, risk of bias for all-cause mortality may be very different than for a patient-reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.
Assesment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the Cochrane review.

Measures of treatment effect

We will analyse dichotomous data as risk ratios and continuous data as mean difference, or standardised mean difference for results across studies with outcomes that are conceptually the same but measured in different ways. We will enter data presented as a scale with a consistent direction of effect. We will combine all the data for the outcomes measures provided that the intervention lasted for 12 weeks or more irrespective of the differences in times at which outcomes are calculated between trials.

We will undertake meta-analyses only where this is meaningful, i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense. We will narratively describe skewed data reported as medians and interquartile ranges.

Unit of analysis issues

The unit of analysis is based on the individual participant (unit to be randomised for interventions to be compared), that is the number of observations in the analysis should match the number of individuals randomised (Higgins 2003).

Where multiple trial arms are reported in a single trial, we will include only the arms relevant to this review. If two or more comparisons (e.g. drug A versus drug B versus placebo) are suitable for inclusion in the same meta-analysis we will combine the relevant intervention groups together or relevant control groups together, or both, as appropriate to create a single pair-wise comparison as recommended in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If this is not possible we will follow alternative methods described in the same chapter.

We will consider only first period data from eligible randomised cross-over studies.

Dealing with missing data

We will report drop-out rates in the 'Characteristics of included studies' table and we will use intention-to-treat analysis (Higgins 2011). We plan to contact trial authors for missing data.

Assessment of heterogeneity

We will consider clinical heterogeneity before making a decision whether to pool studies. We will only perform meta-analysis if participants, interventions and comparisons are sufficiently similar. We will use the I² statistic to measure statistical heterogeneity among the trials in each analysis. If we identify substantial unexplained heterogeneity we will report it and explore possible causes by prespecified subgroup analysis. We will use the following thresholds as a rough guide for interpretation of I², as described in Higgins 2011.

0% to 40%: might not be important.

30% to 60%: may represent moderate heterogeneity.

50% to 90%: may represent substantial heterogeneity.

75% to 100%: considerable heterogeneity.
Assessment of reporting biases

If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small study biases.

Data synthesis

We will use a fixed-effect model in meta-analysis and if heterogeneity is present, compare these results with a those of a random-effects analysis. If the review includes more than one comparison that cannot be included in a single analysis, we will report results for each comparison separately. If the studies have significant heterogeneity and cannot be combined, we will report findings in a narrative form.

We will consider studies of vitamin B complexes as one supplement for the purposes of meta-analysis, taking into account the potential heterogeneity and indirectness of evidence from such analyses when we assess the quality of the evidence.

'Summary of findings' tables

We will create 'Summary of findings' tables using the primary and secondary outcomes. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence (studies that contribute data for the prespecified outcomes). We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEproGDT software (GRADEpro 2014). We will justify decisions to downgrade or upgrade the quality of the evidence using footnotes and where necessary we will make comments to aid readers' understanding of the review.
Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses.


Types of vitamin B supplement.


Children under 18 and adults.

We will use the primary outcome in subgroup analyses in Review Manager (RevMan 2014).
Sensitivity analysis

We plan to perform the following sensitivity analyses.

Repeat the analysis excluding studies at high risk of bias (from randomisation or blinding of participants).

If there is one or more very large study, repeat the analysis excluding them to determine how much they dominate the results.

Repeat the analysis using a random-effects model if heterogeneity is present.
Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies. Our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.
Acknowledgements

The authors would like to acknowledge the editorial support from Cochrane Neuromuscular and the Information Specialist (Angela Gunn) who developed the search strategy in collaboration with the review authors.

Some sections of the review are based on Ang 2008 and on a protocol template originally developed by Cochrane Airways and adapted by Cochrane Neuromuscular.

This project was supported by the National Institute for Health Research (NIHR) via Cochrane Infrastructure funding to Cochrane Neuromuscular. The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service, or the Department of Health. Cochrane Neuromuscular is also supported by the MRC Centre for Neuromuscular Diseases.

Appendices
Appendix 1. DRAFT MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 2014="" 4="" october="" to="" week="">
Search Strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (397786)
2 controlled clinical trial.pt. (90503)
3 randomized.ab. (293092)
4 placebo.ab. (154196)
5 drug therapy.fs. (1777958)
6 randomly.ab. (205733)
7 trial.ab. (305213)
8 groups.ab. (1307610)
9 or/1-8 (3350308)
10 exp animals/ not humans.sh. (4082107)
11 9 not 10 (2854354)
12 exp Diabetes Mellitus/ (328635)
13 diabet$.mp. (462274)
14 12 or 13 (463642)
15 exp Peripheral Nervous System Diseases/ (119617)
16 15 or (neuropath$ or polyneuropath$).mp. (182081)
17 14 and 16 (20728)
18 Diabetic Neuropathies/ (12459)
19 17 or 18 (20728)
20 exp Vitamin B Complex/tu [Therapeutic Use] (23726)
21 (aminonicotinamide or cobamide$1 or cyanocobalamin or flavin mononucleutide or flavin adenine dinucleotide or fursultiamin or hydroxycobalamin or hydroxocobalamine).mp. (7678)
22 (methylcobalamin or nicorandil or nicotinic acid or nikethamide or pyridoxal or pyridoxamine or pyridoxine or riboflavin or thiamine or vitamin b complex).mp. (54422)
23 or/20-22 (74266)
24 11 and 19 and 23 (203)
25 remove duplicates from 24 (199)
Contributions of authors
HK drafted the protocol. All the other authors provided feedback on it.
Declarations of interest
None known.
Sources of support
Internal sources

None, Other.
External sources

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http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD012237/full

SYSTEM REVEALS HOW OUR BRAINS BODIES CHANGE AS WE FALL ASLEEP

Massachusetts General Hospital (MGH) investigators have developed a system to accurately track the dynamic process of falling asleep, something has not been possible with existing techniques. In their report in the October issue of the open-access journal PLOS Computational Biology, the research team describes how combining key physiologic measurements with a behavioral task that does not interfere with sleep onset gives a better picture of the gradual process of falling asleep. In addition to being a powerful tool for future research, the system could provide valuable insight into diagnosing and understanding sleep disorders.

"While our personal experience tells us that falling asleep is a gradual process, current clinical methods only define a single point in time at which one has fallen asleep," says Michael Prerau, PhD, of the MGH Department of Anesthesia, Critical Care and Pain Management, lead author of the report. "Our new research shows that it's not simply when you fall asleep that's important, it's how you fall asleep that really matters. We now have the power to chart the entire trajectory of your neurological, physiological and behavioral activity as you transition from wake to asleep, rather than simply reporting the time it takes."

In their report, the investigators describe developing a method that continuously estimates the degree to which an individual is awake at each point during the sleep onset process. "This is a real paradigm shift in the way we study sleep onset," says Patrick Purdon, PhD, MGH Department of Anesthesia, Critical Care and Pain Management and senior author of the study. "By quantifying the dynamic changes in brain activity and behavior during the transition from wakefulness to sleep, we now have a rigorous framework with which to study disorders of sleep onset, such as insomnia or narcolepsy."

To link changes in brain activity to loss of consciousness during sleep onset, the investigators developed a new, minimally disruptive means of tracking behavior as someone falls asleep. Earlier methods either used tasks in which a participant was asked to respond to auditory cues, something that could disrupt falling asleep, or actigraphy -- the method of measuring movement used in most clinical sleep devices and consumer wearables, which cannot distinguish between sleep and motionless wakefulness. To get around these problems the investigators developed an ingenious new behavioral task that is accurate without disturbing sleep.

Instead of responding to a sound, a participant holds a small rubber "stress ball" in one hand and is asked to squeeze the ball with every intake of breath and release it when exhaling. A special glove on that hand and electrodes on the forearm measure both the timing and the force of each squeeze. In this way, the participant's own breathing acts as the stimulus, and the squeezes act as the behavioral response. Tracking how well ball squeezes are aligned with an individual's breathing reflects a gradual process during which more and more squeezes are mistimed or totally absent. Measuring the force exerted by the forearm muscle also reflects how the strength of the squeezing motion drops with sleep onset.

At the same time as the ball-squeeze measurements are taken, EEG readings track three brain wave patterns previously associated with falling asleep, decreasing power in the alpha frequency range and increasing power in delta and theta frequencies. The combination of all of these measures -- the timing and strength of ball squeezes and the change in brain wave levels -- is used to calculate what the investigators call the wake probability, an estimate of the degree to which a participant is awake during the process of sleep onset.

Testing their model in healthy volunteers over several nights not only provided more accurate results than did traditional methods of sleep determination, it also revealed differences in the way sleep onset occurs in different individuals. Current clinical criteria define sleep as beginning when the power of an individual's alpha-range brainwaves disappears. While seven of the nine study participants followed this pattern, two participants continued to correctly time their ball squeezes for several minutes after alpha levels had dropped. Only when the power in their brainwaves at the theta and delta frequencies had risen did both the behavioral and physiological measures indicate that they were asleep.

"These participants continued to respond to the task, even though current clinical measures would say they were still asleep, which was clearly not the case," says Prerau. "These results suggest that it is the presence of delta and theta power, rather than the lack of alpha power, that is necessary for the cessation of behavior. We may need to carefully re-examine the way sleep onset is defined, since behavior is an essential component of the story that is not measured clinically."

By characterizing the trajectory of the sleep onset process in healthy individuals, Prerau and Purdon believe this study will ultimately shed light on what happens in patients who have trouble falling asleep, leading to an improved ability to understand and diagnose sleep disorders as well as to more precisely measure the effect of sleep medications. This method could also be used to track drowsiness in situations in which alertness is vital.

CAN WE RESTART THE HEART

In a way, trying to repair age-related heart damage and trying to fight cancer are opposite problems. Your heart cells' ability to regenerate themselves and proliferate into new, young cells degrades as you get older. They simply lose their proficiency at cell division. Cancer cells, on the other hand, are too good at proliferating. They don't know when to stop, and the overgrowth results in tumors.

This is all very simplified, of course, but it's the basic model described by Mark Sussman, chief research scientist at the San Diego State University Heart Institute, who was recently selected by the American Heart Association's Basic Cardiovascular Science division to receive this year's Distinguished Achievement Award.

The heart in particular seems to be resistant to developing cancerous cells.

"When's the last time you heard of anyone having heart cancer? It's almost unheard of," said Sussman.

That's not surprising from an evolutionary standpoint. If heart cells make a grave transcription error during cell division and your ticker ticks its last tock, there's no fixing the problem. So it makes sense that heart cells are incredibly careful when it comes to proliferating.

But it's this very meticulousness that makes heart disease such an intractable problem, Sussman explained. Over time, the cells burn themselves out. Their ability to repair themselves and generate fresh replacements gets progressively worse. By the time you reach old age and start experiencing symptoms of age-related heart disease, your cardiac cells are running on fumes and aren't able to properly divide into new cells.

"There's a razor's edge balancing cellular aging and cancer risk," he said.

What if you could use biotechnology to walk that razor's edge? To use the proliferative and survival properties of cancer-prone cells to rejuvenate cardiac progenitor cells -- a rare type of stem cell that replicates indefinitely into new heart cells--and get them dividing again, without forming tumors?

That's the aim of one arm of Sussman's research at SDSU. Sussman and his colleagues published a paper in the May 29 issue of the Journal of Biological Chemistry exploring the results of taking an enzyme, Pim, known to be associated with growth and survival of certain types of cancer cells, and causing it to be overexpressed in cardiac progenitor cells in mice.

In healthy cells, Pim helps facilitate chromosome splitting, a key part of the cellular division process.

The gene that encodes the production of this enzyme, PIM1, is what's known as a proto-oncogene. That means that by itself, the gene doesn't cause cancer. But when it teams up with another gene, Myc, tumors are likely to form.

Fortunately, the Pim/Myc combination isn't an issue in heart progenitor cells, meaning you could tweak those cells to overexpress the PIM1 gene without raising the risk of cancer.

That's exactly what Sussman's team did. They modified mouse heart progenitor cells to overexpress PIM1 in specific locations within the cell, targeting specific locations with more of the critical Pim enzyme in hopes that it would protect against aging-related heart disease.

And it worked. Compared to controls, the mice with overexpressed PIM1 lived longer and showed stronger cell proliferation. But interestingly, the way it worked was different depending on where in the cell the gene was overexpressed.

If the researchers caused PIM1 to be overexpressed in the progenitor cell's nucleus, they saw increased proliferation into new cells. If they overexpressed the gene in a different region of the cell, the mitochondria, they found that the enzyme inhibited the cell's natural self-destruct signals, causing them to live longer.

One technique enhanced cell division, the other warded off cell death. In humans, depending on a person's individual circumstance, either or both of these effects might help restore their cardiac cells to a younger, healthier state.

Sussman and his colleagues have replicated the results with human tissue obtained from people whose hearts have failed and who are living on a ventricular assist device that pumps their blood for them. The research team is currently trying to obtain funding to do human clinical trials wherein they obtain a patient's own cardiac progenitor cells, modify them to overexpress PIM1, then put them back into the patient's heart in hopes of rejuvenating the tissue and spurring the heart to repair itself.

"We're trying to dial back the clock to when their cells had more regenerative potential," Sussman said. "By understanding how and where Pim affects these cells, we can create specialized Pim molecules that get you all the benefits of youthfulness without the risk of cancer."

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