on 31-Dec-2023 (Sun)

I added "start": "webpack-dev-server --port 8085" under "scripts" object in package.json to change default webpack dev server port to 8085.

 "scripts" : { ... "start" : "webpack-dev-server --port 8085" , "build" : "webpack --mode=production" , ...
}

"@mui/x-data-grid": "^6.2.1"

onSelectionModelChange is now onRowSelectionModelChange

COPD patients have a 20-fold increase in alveolar macrophages (AMs) in alveoli, bronchioles, and small airways.62,63 Because AMs are a major source of inflammatory cytokines and growth factors, recruitment of inflammatory cells into the lung accelerates the vicious inflammatory cycle produced by microaspiration.

In spite of increased numbers, AMs have impaired phagocytosis, reducing their ability to clear bacteria from the lower airway, thereby causing further inflammation and oxidative stress.64–67

A proinflammatory subset of CD4+ T cells, known as Th17 cells, are frequently found at the mucosal interface and are implicated in the pathogenesis of chronic inflammatory conditions, including COPD and asthma

Neutrophils are then recruited and activated by nonresolving pulmonary inflammation, particularly during exacerbations. Neutrophil elastase and metalloproteinases lead to lung parenchyma destruction

More recently, there has been increasing attention to the role of eosinophils in COPD. Eosinophilic airway inflammation occurs in approximately 15% to 40% of individuals with COPD.78 Increased eosinophils are a risk factor for exacerbation after deescalation of inhaled corticosteroid therapy.79 During exacerbations, there is an increase in the number of eosinophils in sputum.80

Elevated eosinophils are associated with patients’ responsiveness to corticosteroids during both acute exacerbations and stable disease.79,81–83 High eosinophils may define a distinct host Th2-predominant endotype with asthma overlap that is more responsive to corticosteroids.84

Investigations that have excluded patients with a history of asthma have shown that high blood eosinophils do not predict steroid responsiveness.85 The use of eosinophil levels in directing therapy requires further investigation.86

Systemic comorbidities such as vascular disease are major risk factors for mortality during COPD exacerbations.90,91 Systemic inflammation caused by COPD is also hypothesized to be associated with anemia, osteoporosis, depression, and metabolic syndrome.92–94

Increased bacterial colonization of the lower airways in COPD occurs as a result of chronic microaspiration, impaired clearance of bacteria, and frequent COPD exacerbations.95,96

Patients with COPD frequently have microaspiration owing to gastroesophageal reflux caused by incoordination between breathing and swallowing.97–99

Impaired mucocili- ary clearance in smokers reduces the ability to clear oral microbes from the lower airways, exacerbating inflammation.

Inhaled medications may also carry oral bacteria into the lower airway.

This vicious cycle could explain the association of poor oral health and increased airway bacterial load, COPD exacerbations, and reduced lung function.100–104

High bacterial burden in the lower airway is associated with accelerated FEV1 decline, more comorbidity, more exacerbations, and worse symptoms during exacerbations.23,110–113

In stable COPD, the rates of positive routine bacterial cultures of sputum vary between 22% and 83%.114–116 However, interpreting sputum culture is difficult because of upper airway contamination, which reduces specificity, and failure to grow fastidious bacteria from the complex lower airway microbiome, which reduces sensitivity.

In stable COPD, non–potential pathogenic microorganisms (non-PPMs) are isolated much more frequently than potential pathogenic microorganisms (PPMs).114 Non-PPMs are usually oropharyngeal microbes such as Corynebacterium spp., Neisseria spp., Enterococcus spp., coagulase- negative staphylococci, viridans-group streptococci, and fungi such as Candida spp.114

The lower airways of healthy individuals harbor low levels of oral bacteria such as Prevotella spp. and Veillonella spp.123,124 Culture-independent techniques have challenged the dogma that the lower airway is normally sterile, and provide evidence that there are residential organisms, especially in individuals with already damaged lungs.

Important to note, enrichment of the lower airway microbiota with oral bacteria anaerobes is associated with augmented lung inflammation characterized by a Th17 phenotype.125

With culture or polymerase chain reaction (PCR) techniques to assess sputum, the most commonly found respiratory virus is respira- tory syncytial virus (RSV), found in up to 23.5% of patients with COPD, followed by non-RSV viruses, such as rhinovirus, coronavirus, and parainfluenza virus, in 16.2% of samples.131

Two-thirds of patients with a COPD exacerbation have bacteria, viruses, or both cultured from lower airway secretions. Aerobic bacteria are isolated in one-half of patients, respiratory viruses are isolated in one-third, and bacterial-viral coinfection is present in one-quarter of patients with acute exacerbations.58,134

Acquisition of a new bacterial strain frequently precedes AECOPD.106,119,135,138,139 The increase in total bacterial load during a COPD exacerbation is relatively small compared with the total bacterial load.138

H. influenzae, S. pneumoniae, and M. catarrhalis are the bacterial pathogens most commonly isolated during COPD exacerbations. The same three also colonize stable COPD patients, and higher bacterial loads have been associated with AECOPD.58,117,118,135–138

Individuals with greater degrees of functional impairment, recent antibiotic use, or systemic steroid therapy have higher rates of isolation of gram-negative bacteria such as Pseudomonas aeruginosa, Stenotro- phomonas maltophilia, and members of the Enterobacteriaceae family from sputum.141,142

Patients with an FEV1 > 35% of predicted value and no systemic steroid or antibiotic use within the preceding 3 months have a low probability of Enterobacteriaceae or P. aeruginosa in sputum culture.142 H. influenzae and P. a e r u g i n o s a are more common in patients with poorer lung function.137

Polymicrobial exacerbations occur with advanced pulmonary dysfunction and severe exacerbations.134,143

The role of “atypical” bacterial pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila in exacerbation is poorly defined, but they are rarely found in AECOPD.56,131,144

When serology or M. pneumoniae antigen detection has been used to indicate the presence of M. pneumoniae as a pathogen, PCR and culture frequently do not confirm its presence.131,146,147

Rhinovirus is the virus frequently associated with AECOPD and is present approximately 20% to 34% of the time.131,134,150 Coronavirus, parainfluenza virus, adenovirus, influenza virus, and human metapneu- movirus also occur but are less prevalent.143,150

It is likely that viruses and bacteria induce independent inflammatory pathways, accounting for more severe presentations and poorer outcome of patients with coinfection

Short-acting bronchodilators are preferred because they allow titration of the dose required and because there is no clinical trial that has evaluated the use of long–acting bronchodilators during AECOPD. Although for sicker patients nebulized bronchodilators are routinely used in the hospital, data suggest that similar bronchodilator effects occur with metered-dose inhalers.156

Let’s summarize how git rebase --onto is working.

A 10- to 14-day course of sys- temic corticosteroids reduces treatment failure by 46% during both inpatient and outpatient management of COPD exacerbations.157 Systemic corticosteroids are preferred during an exacerbation because they reduce recovery time, improve lung function, and increase arte- rial oxygenation.158,159,160,161,162

Although there are no data to support a specific dose or route of administration for steroids, GOLD guidelines recommend 30 to 40 mg of oral prednisolone per day for 10 to 14 days.5,162–164

Early antibiotic treatment of AECOPD in both the outpatient and inpatient settings has become nearly routine in clinical practice even though the role of bacteria in many cases of AECOPD is uncertain.

Studies evaluating the effect of antibiotic treatment are mostly small and are difficult to compare because of heterogeneous patient populations, diverse outcome measures, and varied definitions of failure.

Two meta-analyses and a Cochrane review concluded that antibiotics improve outcome in AECOPD in inpatients, especially those requiring ICU admission.157,165,166

Among hospitalized patients, antibiotics reduced hospital mortality by 78%.167–169 Antibiotics also led to improved peak expiratory flow rate by 22%.170 The largest study to date evaluating antibiotic efficacy is a retrospective cohort of 84,621 inpatients from 413 acute-care centers in the United States.171 Administra- tion of antibiotics within the first 48 hours reduced the need for mechanical ventilation after 2 hospital days (1.07% vs. 1.80%), lowered rates of inpatient mortality (1.04% vs. 1.59%), reduced readmissions (7.91% vs. 8.79%), and produced fewer treatment failures (9.77% vs. 11.75%). However, there was a significantly higher rate of Clostridioides difficile (formerly Clostridium difficile) in patients who were treated with antibiotics (0.19% vs. 0.94%). The weight of evidence supports antibiotic use for hospitalized patients; particularly those admitted to the ICU

As opposed to relatively high-quality evidence supporting the use of antibiotics in the inpatient setting, there has been less convincing evidence to recommend antibiotics for outpatients

The capacity of an AWGN channel (in bits per second) is given by

\(C = B \log_{2}(1+S/N)\)

where:
- \(B\) is the bandwidth used to convey the bit sequence (in Hertz),
- \(S = \lim_{T\rightarrow\infty} \frac{1}{T}\int^{T}_{0}|v(t)|^{2}dt\) is the signal power (in Watts),
- \(N = \lim_{T\rightarrow\infty} \frac{1}{T}\int^{T}_{0}|n(t)|^{2}dt=\sigma^{2}\) is the noise power (in Watts),
- \(S/N\) is the Signal Noise Ratio (SNR), which may be expressed in decibels as \(10 \log_{10}(S/N)\).

In a retrospective cohort outpatient study of 270 patient visits (with relapse defined as a return visit within 14 days), antibiotics reduced the relapse rate to 19% (50/270) compared with 32% (29/92) among patients who did not receive antibiotics. Patients who received amoxicillin, however, had an even higher relapse rate of 54% (20/37) compared with those who did not receive antibiotics.175

Doxycycline may not provide similar benefits. A very recent randomized, double-blind, placebo-controlled study comparing 7 days of doxycycline with placebo for outpatients receiving oral prednisolone among patients with GOLD stage 1 to 3 disease demonstrated neither a better initial response (87% in the doxycycline group vs. 83% in the placebo group) nor an increased time to second exacerbation (161 days vs. 138 days).177

The authors of the GOLD guidelines note that treatment with antibiot- ics is controversial but recommend antibiotic therapy for patients who have AECOPD who meet one of the following criteria: (1) have all three “cardinal” symptoms—increased dyspnea, increased sputum volume, and increased sputum purulence; (2) have two of the cardinal symptoms if increased purulence of sputum is one of the two symptoms; (3) have severe exacerbation that requires mechanical ventilation (invasive or noninvasive).5

Although the use of bacterial cultures for treatment of AECOPD is debated, the use of purulence to define the need for antibiotics is based on several studies demonstrating a relationship between sputum color and/or neutrophils and positive bacterial cultures.192–195 Sputum purulence has been an excellent guide for antibiotic use in several studies. In one, if sputum purulence was not present and antibiotics were withheld, therapy in only 2 of 32 patients failed.195

It is clear that many patients are prescribed antibiotics who do not need them, but the current state of knowledge does not clearly define the group who will be harmed more than they will be helped by a course of antibiotics.

Among the more commonly studied antibiotics are macrolides (azithromycin and clarithromycin), second-generation cephalosporins (cefuroxime, cefpodoxime, cefdinir), penicillin or penicillinase inhibitors (ampicillin-clavulanate), quinolones (ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin), trimethoprim- sulfamethoxazole, and tetracyclines (doxycycline).

An evaluation of 19,608 patients who were treated with either a quinolone antibiotic (13,469 patients) or macrolide antibiotic (6,139 patients) taken from a larger retrospective cohort study of hospitalized patients with AECOPD showed similar rates of treatment success, although less diarrhea occurred in the macrolide cohort.204

There may be higher relapse rates when acute exacerbations are treated with amoxicillin compared with other antibiotics.175

A sputum sample is not recommended routinely in either the GOLD guidelines or those of the American College of Physicians–American Society of Internal Medicine and the American College of Chest Physicians.5,205 Sputum cultures and Gram stains are not reliable in terms of indicating the infecting pathogen. Furthermore, early sputum cultures do not seem to affect outcome with antibiotic treatment among inpatients.171 An exception to this recommendation should be considered for patients in whom prior therapy has failed and patients at high risk for infection due to Enterobacteriaceae or P. aeruginosa.

However, because up to one-fifth of patients hospitalized for community-acquired pneumonia (CAP) have normal admission chest films but develop an infiltrate within 48 hours, providers may choose to dismiss a normal chest radiograph and prescribe antibiotics.206

Despite increasing resistance to many of the older antibiotics, patients still respond to them clinically. Trimethoprim-sulfamethoxazole and ciprofloxacin were equally effective in a double-blind trial among patients with severe AECOPD requiring mechanical ventilation.208 Surprisingly, bacterial susceptibility did not predict clinical success.208 This may be due to the poor sensitivity and specificity of sputum samples in defining the bacteria that caused the AECOPD. Alternately, AECOPD may be driven by changes of a complex lower airway microbiome and not by a single microorganism.

A regimen of 5 days of therapy with a quinolone, second-generation cephalosporin, or macrolide is as efficacious as and is associated with fewer adverse reactions than 7 days of anti- microbial therapy.212–215 The GOLD guidelines currently recommend 5 to 7 days of therapy.

Although there are no comparable inpatient trials, durations of therapy have varied between 7 and 14 days; 10 days of treatment have been used in studies of hospitalized AECOPD patients.168,208 Eight days of therapy, which is currently recommended for ventilator-associated pneumonia, may suffice even in critically ill patients.216

Nonimmunized people with COPD who have had close family contact with a person with influenza should receive chemoprophylaxis with a neuraminidase inhibitor.217

Patients with COPD would be considered at high risk for severe influenza infection and should be offered neuraminidase inhibitors such as oseltamivir or zanamivir when they develop an influenza-like illness during influenza season, even in the setting of a negative rapid virus detection study result.217

The goal of therapy is to avoid acute exacerbations because these are associated with accelerated declines in lung function.133 β2-Agonists (long-acting β2-agonists [LABAs]) and anticholinergic bronchodilators (LAMAs) frequently combined in a single inhaler are effective in reducing exacerbations.85

Inhaled corticosteroids do not reduce mortality but do reduce COPD exacerbations,221 decrease inflammation, and stabilize lung function in moderate and severe COPD.222 Unfortunately, inhaled corticosteroids increase the risk for pneumonia, which must be balanced with the benefit of less frequent exacerbations.221,223

Corticosteroids in steady-state COPD are restricted to adjunctive therapy complementing long-acting bronchodilators in more severe cases of COPD and may be most effective in patients with characteristics of both COPD and asthma.220

A large-scale randomized, placebo-controlled study of azithromycin 250 mg daily for 1 year reduced AECOPD from 1.82 exacerbations per patient-year in the placebo group to 1.48 exacerbations per patient-year in the azithromycin group. Antibiotic treatment also extended time to first exacerbation from 174 to 266 days and improved quality of life.232 The azithromycin group, however, had more hearing loss.232 Among patients who became colonized, macrolide resistance occurred in 81% of the treated group versus 41% of the placebo control. Important to note, this trial excluded patients with cardiovascular risks including a resting heart rate >100 beats/min, prolonged QT (QTc) interval, or medications that increase the QTc interval.

The mechanisms that reduce exacerbation go beyond their antibacterial effect. These drugs are directly antiinflammatory, decreasing proinflammatory cytokine production, adhesion molecules, and reactive oxygen species.239,240

In addition, intermittent short courses of macrolides produced a fourfold increase in S. pneumoniae within 6 months.238

For patients with low cardiovascular risk and frequent exacerbation in spite of adequate routine therapy, macrolides should be considered (see Tab l e 66 . 2).244 Intermittent (thrice-weekly) and daily azithromycin appear to provide similar benefits.245

Long-term macrolides have also been studied in cystic fibrosis and bronchiectasis, where they have led to fewer exacerbations of disease and stabilization of lung function.242,243

Another strategy to prevent AECOPD is intermittent antibiotic therapy. Moxifloxacin 400 mg for 5 days every 8 weeks for a total of six courses reduced the odds of exacerbation by 20% in the intention- to-treat analysis of the enrolled COPD patients and by 45% among patients with baseline purulent sputum. The authors reported no increased resistance to moxifloxacin among cultured bacteria but did find more gastrointestinal problems (4.7% with moxifloxacin vs. 0.7% with placebo).246 Further research is needed to confirm that the benefits of this approach outweigh the risks of resistance and C. difficile colitis before this strategy gains widespread use.

Six of the seven studies evaluating effectiveness of the influenza vaccine revealed that seasonal influenza vaccine decreased the frequency of AECOPD, hospitalizations, outpatient visits, and all-cause and respiratory mortal- ity.249 Two other studies reported since the systematic literature review confirmed these findings.250,251

Some observational studies have demonstrated a decrease in pneumococcal bacteremia in the elderly and in hospitalization for pneumonia and mortality among elderly patients with chronic lung disease.252,253 Others have not been able to corroborate these findings.254 Based on a meta-analysis including 12 studies, there was a significant reduction in the likelihood of developing CAP but not specifically pneumococcal pneumonia, and a decrease in the likelihood of COPD exacerbation.255 However, there was neither a decrease in all-cause mortality or cardiorespiratory mortality nor in the likelihood of all-cause or cardiorespiratory hospitalization. Studies evaluating the recent guidelines for sequencing the PPSV23 and the PCV13 vaccines in the COPD population are warranted.256

Several studies have reported that there is an additive effect when both the influenza vaccine and pneumococcal vaccine are used among patients with COPD. There was a significant reduction in hospitalization (63%) and in mortality (81%) when both vaccines were administered compared with no vaccine.257 Two more recent cohort studies from Japan demonstrated better outcomes when both influenza vaccine and pneumococcal vaccine were administered compared with influenza vaccine alone.258,259

High rates of herpes zoster infection, due to either immune alterations or frequent steroid use, have been reported in patients with COPD.260,262 In the population-based study by Yang and colleagues, the adjusted hazard ratio was 1.68 for COPD patients not taking steroids compared with the general population.262 The hazard ratio increased to 2.09 for COPD patients taking inhaled corticosteroids, and was highest for those on oral steroids (adjusted hazard ratio of 3.00).

Zoster vaccine should be administered to patients with COPD per current ACIP guidelines.

Hamming encoding is achieved using the generator matrix \(\mathbf{G}\) and the modulo-2 matrix product.

The generator matrix of Hamming Encoding: \(\displaystyle \mathbf{G}=\left[\begin{array}{llll}1 & 1 & 0 & 1 \\1 & 0 & 1 & 1 \\1 & 0 & 0 & 0 \\0 & 1 & 1 & 1 \\0 & 1 & 0 & 0 \\0 & 0 & 1 & 0 \\0 & 0 & 0 & 1\end{array}\right]\).

The modulo-2 matrix product: \(\displaystyle\begin{array}{|c|c|c|}\hline a & b & a \oplus b \\\hline 0 & 0 & 0 \\\hline 0 & 1 & 1 \\\hline 1 & 0 & 1 \\\hline 1 & 1 & 0 \\\hline\end{array}\)

Hamming decoding can mitigate the bit errors using the parity check matrix \(\mathbf{H}\) and the modulo-2 matrix product.

The parity check matrix of Hamming Decoding: \(\displaystyle \mathbf{H}=\left[\begin{array}{lllllll}0 & 0 & 0 & 1 & 1 & 1 & 1 \\0 & 1 & 1 & 0 & 0 & 1 & 1 \\1 & 0 & 1 & 0 & 1 & 0 & 1\end{array}\right]\).

Using the resultant \(n − k\) = 3-bit syndrome \(\mathbf{s}\), the Hamming decoder decides if it thinks there are any bit errors in \(\hat{\mathbf{y}}\):
- If the syndrome is \(\mathbf{s} = \begin{array}{ccc}[ 0 &0 &0]\end{array}^{T}\) then the Hamming decoder thinks there are no bit errors in \(\hat{\mathbf{y}}\) (it may be wrong though). In this case, it outputs \(\hat{\mathbf{x}} = \begin{array}{cccc}[ \hat{y}_{3} &\hat{y}_{5} &\hat{y}_{6} &\hat{y}_{7} ]\end{array}^{T}\) since \(y_{3} = x_{1}\), \(y_{5} = x_{2}\), \(y_{6} = x_{3}\) and \(y_{7} = x_{4}\) in \(\mathbf{G}\).
- If the syndrome \(\mathbf{s}\) is not equal to \(\begin{array}{ccc}[ 0 &0 &0]\end{array}^{T}\) then its 3-bit number is converted into a decimal number \(i ∈ [1, 7]\). In this case, the Hamming decoder thinks that the ith bit in \(\hat{\mathbf{y}}\) has been flipped by a bit error (it may be wrong though). The Hamming decoder flips the \(i\)th bit in \(\hat{\mathbf{y}}\) before outputting \(\hat{\mathbf{x}}=\left[\begin{array}{llll}\hat{y}_3 & \hat{y}_5 & \hat{y}_6 & \hat{y}_7\end{array}\right]^T\). If there are multiple bit errors in the received codeword \(\hat{\mathbf{y}}\), the syndrome \(\mathbf{s}\) identifies which bit of \(\hat{\mathbf{y}}\) can be toggled to give the legitimate permutation of \(\mathbf{y}\) that is most similar.