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US Senators lined up to meet PM Modi and gave him standing Ovation. Video- Speech to US Congress

This is the 17th installment of The Rationalist, my column for the Times of India.

One of my favourite English words comes from chess. If it is your turn to move, but any move you make makes your position worse, you are in ‘Zugzwang’. Narendra Modi was in zugzwang after the Pulwama attacks a few days ago—as any Indian prime minister in his place would have been.

An Indian PM, after an attack for which Pakistan is held responsible, has only unsavoury choices in front of him. He is pulled in two opposite directions. One, strategy dictates that he must not escalate. Two, politics dictates that he must.

Let’s unpack that. First, consider the strategic imperatives. Ever since both India and Pakistan became nuclear powers, a conventional war has become next to impossible because of the threat of a nuclear war. If India escalates beyond a point, Pakistan might bring their nuclear weapons into play. Even a limited nuclear war could cause millions of casualties and devastate our economy. Thus, no matter what the provocation, India needs to calibrate its response so that the Pakistan doesn’t take it all the way.

It’s impossible to predict what actions Pakistan might view as sufficient provocation, so India has tended to play it safe. Don’t capture territory, don’t attack military assets, don’t kill civilians. In other words, surgical strikes on alleged terrorist camps is the most we can do.

Given that Pakistan knows that it is irrational for India to react, and our leaders tend to be rational, they can ‘bleed us with a thousand cuts’, as their doctrine states, with impunity. Both in 2001, when our parliament was attacked and the BJP’s Atal Bihari Vajpayee was PM, and in 2008, when Mumbai was attacked and the Congress’s Manmohan Singh was PM, our leaders considered all the options on the table—but were forced to do nothing.

But is doing nothing an option in an election year?

Leave strategy aside and turn to politics. India has been attacked. Forty soldiers have been killed, and the nation is traumatised and baying for blood. It is now politically impossible to not retaliate—especially for a PM who has criticized his predecessor for being weak, and portrayed himself as a 56-inch-chested man of action.

I have no doubt that Modi is a rational man, and knows the possible consequences of escalation. But he also knows the possible consequences of not escalating—he could dilute his brand and lose the elections. Thus, he is forced to act. And after he acts, his Pakistan counterpart will face the same domestic pressure to retaliate, and will have to attack back. And so on till my home in Versova is swallowed up by a nuclear crater, right?

Well, not exactly. There is a way to resolve this paradox. India and Pakistan can both escalate, not via military actions, but via optics.

Modi and Imran Khan, who you’d expect to feel like the loneliest men on earth right now, can find sweet company in each other. Their incentives are aligned. Neither man wants this to turn into a full-fledged war. Both men want to appear macho in front of their domestic constituencies. Both men are masters at building narratives, and have a pliant media that will help them.

Thus, India can carry out a surgical strike and claim it destroyed a camp, killed terrorists, and forced Pakistan to return a braveheart prisoner of war. Pakistan can say India merely destroyed two trees plus a rock, and claim the high moral ground by returning the prisoner after giving him good masala tea. A benign military equilibrium is maintained, and both men come out looking like strong leaders: a win-win game for the PMs that avoids a lose-lose game for their nations. They can give themselves a high-five in private when they meet next, and Imran can whisper to Modi, “You’re a good spinner, bro.”

There is one problem here, though: what if the optics don’t work?

If Modi feels that his public is too sceptical and he needs to do more, he might feel forced to resort to actual military escalation. The fog of politics might obscure the possible consequences. If the resultant Indian military action causes serious damage, Pakistan will have to respond in kind. In the chain of events that then begins, with body bags piling up, neither man may be able to back down. They could end up as prisoners of circumstance—and so could we.

***

Also check out:

Why Modi Must Learn to Play the Game of Chicken With Pakistan—Amit Varma
The Two Pakistans—Episode 79 of The Seen and the Unseen
India in the Nuclear Age—Episode 80 of The Seen and the Unseen

© 2007 IndiaUncut.com. All rights reserved.
India Uncut * The IU Blog * Rave Out * Extrowords * Workoutable * Linkastic

This is the 22nd installment of The Rationalist, my column for the Times of India.

Trade wars are on the rise, and it’s enough to get any nationalist all het up and excited. Earlier this week, Narendra Modi’s government announced that it would start imposing tariffs on 28 US products starting today. This is a response to similar treatment towards us from the US.

There is one thing I would invite you to consider: Trump and Modi are not engaged in a war with each other. Instead, they are waging war on their own people.

Let’s unpack that a bit. Part of the reason Trump came to power is that he provided simple and wrong answers for people’s problems. He responded to the growing jobs crisis in middle America with two explanations: one, foreigners are coming and taking your jobs; two, your jobs are being shipped overseas.

Both explanations are wrong but intuitive, and they worked for Trump. (He is stupid enough that he probably did not create these narratives for votes but actually believes them.) The first of those leads to the demonising of immigrants. The second leads to a demonising of trade. Trump has acted on his rhetoric after becoming president, and a modern US version of our old ‘Indira is India’ slogan might well be, “Trump is Tariff. Tariff is Trump.”

Contrary to the fulminations of the economically illiterate, all tariffs are bad, without exception. Let me illustrate this with an example. Say there is a fictional product called Brump. A local Brump costs Rs 100. Foreign manufacturers appear and offer better Brumps at a cheaper price, say Rs 90. Consumers shift to foreign Brumps.

Manufacturers of local Brumps get angry, and form an interest group. They lobby the government – or bribe it with campaign contributions – to impose a tariff on import of Brumps. The government puts a 20-rupee tariff. The foreign Brumps now cost Rs 110, and people start buying local Brumps again. This is a good thing, right? Local businesses have been helped, and local jobs have been saved.

But this is only the seen effect. The unseen effect of this tariff is that millions of Brump buyers would have saved Rs 10-per-Brump if there were no tariffs. This money would have gone out into the economy, been part of new demand, generated more jobs. Everyone would have been better off, and the overall standard of living would have been higher.

That brings to me to an essential truth about tariffs. Every tariff is a tax on your own people. And every intervention in markets amounts to a distribution of wealth from the people at large to specific interest groups. (In other words, from the poor to the rich.) The costs of this are dispersed and invisible – what is Rs 10 to any of us? – and the benefits are large and worth fighting for: Local manufacturers of Brumps can make crores extra. Much modern politics amounts to manufacturers of Brumps buying politicians to redistribute money from us to them.

There are second-order effects of protectionism as well. When the US imposes tariffs on other countries, those countries may respond by imposing tariffs back. Raw materials for many goods made locally are imported, and as these become expensive, so do those goods. That quintessential American product, the iPhone, uses parts from 43 countries. As local products rise in price because of expensive foreign parts, prices rise, demand goes down, jobs are lost, and everyone is worse off.

Trump keeps talking about how he wants to ‘win’ at trade, but trade is not a zero-sum game. The most misunderstood term in our times is probably ‘trade-deficit’. A country has a trade deficit when it imports more than what it exports, and Trump thinks of that as a bad thing. It is not. I run a trade deficit with my domestic help and my local grocery store. I buy more from them than they do from me. That is fine, because we all benefit. It is a win-win game.

Similarly, trade between countries is really trade between the people of both countries – and people trade with each other because they are both better off. To interfere in that process is to reduce the value created in their lives. It is immoral. To modify a slogan often identified with libertarians like me, ‘Tariffs are Theft.’

These trade wars, thus, carry a touch of the absurd. Any leader who imposes tariffs is imposing a tax on his own people. Just see the chain of events: Trump taxes the American people. In retaliation, Modi taxes the Indian people. Trump raises taxes. Modi raises taxes. Nationalists in both countries cheer. Interests groups in both countries laugh their way to the bank.

What kind of idiocy is this? How long will this lose-lose game continue?

© 2007 IndiaUncut.com. All rights reserved.
India Uncut * The IU Blog * Rave Out * Extrowords * Workoutable * Linkastic

This is the 17th installment of The Rationalist, my column for the Times of India.

One of my favourite English words comes from chess. If it is your turn to move, but any move you make makes your position worse, you are in ‘Zugzwang’. Narendra Modi was in zugzwang after the Pulwama attacks a few days ago—as any Indian prime minister in his place would have been.

An Indian PM, after an attack for which Pakistan is held responsible, has only unsavoury choices in front of him. He is pulled in two opposite directions. One, strategy dictates that he must not escalate. Two, politics dictates that he must.

Let’s unpack that. First, consider the strategic imperatives. Ever since both India and Pakistan became nuclear powers, a conventional war has become next to impossible because of the threat of a nuclear war. If India escalates beyond a point, Pakistan might bring their nuclear weapons into play. Even a limited nuclear war could cause millions of casualties and devastate our economy. Thus, no matter what the provocation, India needs to calibrate its response so that the Pakistan doesn’t take it all the way.

It’s impossible to predict what actions Pakistan might view as sufficient provocation, so India has tended to play it safe. Don’t capture territory, don’t attack military assets, don’t kill civilians. In other words, surgical strikes on alleged terrorist camps is the most we can do.

Given that Pakistan knows that it is irrational for India to react, and our leaders tend to be rational, they can ‘bleed us with a thousand cuts’, as their doctrine states, with impunity. Both in 2001, when our parliament was attacked and the BJP’s Atal Bihari Vajpayee was PM, and in 2008, when Mumbai was attacked and the Congress’s Manmohan Singh was PM, our leaders considered all the options on the table—but were forced to do nothing.

But is doing nothing an option in an election year?

Leave strategy aside and turn to politics. India has been attacked. Forty soldiers have been killed, and the nation is traumatised and baying for blood. It is now politically impossible to not retaliate—especially for a PM who has criticized his predecessor for being weak, and portrayed himself as a 56-inch-chested man of action.

I have no doubt that Modi is a rational man, and knows the possible consequences of escalation. But he also knows the possible consequences of not escalating—he could dilute his brand and lose the elections. Thus, he is forced to act. And after he acts, his Pakistan counterpart will face the same domestic pressure to retaliate, and will have to attack back. And so on till my home in Versova is swallowed up by a nuclear crater, right?

Well, not exactly. There is a way to resolve this paradox. India and Pakistan can both escalate, not via military actions, but via optics.

Modi and Imran Khan, who you’d expect to feel like the loneliest men on earth right now, can find sweet company in each other. Their incentives are aligned. Neither man wants this to turn into a full-fledged war. Both men want to appear macho in front of their domestic constituencies. Both men are masters at building narratives, and have a pliant media that will help them.

Thus, India can carry out a surgical strike and claim it destroyed a camp, killed terrorists, and forced Pakistan to return a braveheart prisoner of war. Pakistan can say India merely destroyed two trees plus a rock, and claim the high moral ground by returning the prisoner after giving him good masala tea. A benign military equilibrium is maintained, and both men come out looking like strong leaders: a win-win game for the PMs that avoids a lose-lose game for their nations. They can give themselves a high-five in private when they meet next, and Imran can whisper to Modi, “You’re a good spinner, bro.”

There is one problem here, though: what if the optics don’t work?

If Modi feels that his public is too sceptical and he needs to do more, he might feel forced to resort to actual military escalation. The fog of politics might obscure the possible consequences. If the resultant Indian military action causes serious damage, Pakistan will have to respond in kind. In the chain of events that then begins, with body bags piling up, neither man may be able to back down. They could end up as prisoners of circumstance—and so could we.

***

Also check out:

Why Modi Must Learn to Play the Game of Chicken With Pakistan—Amit Varma
The Two Pakistans—Episode 79 of The Seen and the Unseen
India in the Nuclear Age—Episode 80 of The Seen and the Unseen

The India Uncut Blog © 2010 Amit Varma. All rights reserved.
Follow me on Twitter.

This is the 22nd installment of The Rationalist, my column for the Times of India.

Trade wars are on the rise, and it’s enough to get any nationalist all het up and excited. Earlier this week, Narendra Modi’s government announced that it would start imposing tariffs on 28 US products starting today. This is a response to similar treatment towards us from the US.

There is one thing I would invite you to consider: Trump and Modi are not engaged in a war with each other. Instead, they are waging war on their own people.

Let’s unpack that a bit. Part of the reason Trump came to power is that he provided simple and wrong answers for people’s problems. He responded to the growing jobs crisis in middle America with two explanations: one, foreigners are coming and taking your jobs; two, your jobs are being shipped overseas.

Both explanations are wrong but intuitive, and they worked for Trump. (He is stupid enough that he probably did not create these narratives for votes but actually believes them.) The first of those leads to the demonising of immigrants. The second leads to a demonising of trade. Trump has acted on his rhetoric after becoming president, and a modern US version of our old ‘Indira is India’ slogan might well be, “Trump is Tariff. Tariff is Trump.”

Contrary to the fulminations of the economically illiterate, all tariffs are bad, without exception. Let me illustrate this with an example. Say there is a fictional product called Brump. A local Brump costs Rs 100. Foreign manufacturers appear and offer better Brumps at a cheaper price, say Rs 90. Consumers shift to foreign Brumps.

Manufacturers of local Brumps get angry, and form an interest group. They lobby the government – or bribe it with campaign contributions – to impose a tariff on import of Brumps. The government puts a 20-rupee tariff. The foreign Brumps now cost Rs 110, and people start buying local Brumps again. This is a good thing, right? Local businesses have been helped, and local jobs have been saved.

But this is only the seen effect. The unseen effect of this tariff is that millions of Brump buyers would have saved Rs 10-per-Brump if there were no tariffs. This money would have gone out into the economy, been part of new demand, generated more jobs. Everyone would have been better off, and the overall standard of living would have been higher.

That brings to me to an essential truth about tariffs. Every tariff is a tax on your own people. And every intervention in markets amounts to a distribution of wealth from the people at large to specific interest groups. (In other words, from the poor to the rich.) The costs of this are dispersed and invisible – what is Rs 10 to any of us? – and the benefits are large and worth fighting for: Local manufacturers of Brumps can make crores extra. Much modern politics amounts to manufacturers of Brumps buying politicians to redistribute money from us to them.

There are second-order effects of protectionism as well. When the US imposes tariffs on other countries, those countries may respond by imposing tariffs back. Raw materials for many goods made locally are imported, and as these become expensive, so do those goods. That quintessential American product, the iPhone, uses parts from 43 countries. As local products rise in price because of expensive foreign parts, prices rise, demand goes down, jobs are lost, and everyone is worse off.

Trump keeps talking about how he wants to ‘win’ at trade, but trade is not a zero-sum game. The most misunderstood term in our times is probably ‘trade-deficit’. A country has a trade deficit when it imports more than what it exports, and Trump thinks of that as a bad thing. It is not. I run a trade deficit with my domestic help and my local grocery store. I buy more from them than they do from me. That is fine, because we all benefit. It is a win-win game.

Similarly, trade between countries is really trade between the people of both countries – and people trade with each other because they are both better off. To interfere in that process is to reduce the value created in their lives. It is immoral. To modify a slogan often identified with libertarians like me, ‘Tariffs are Theft.’

These trade wars, thus, carry a touch of the absurd. Any leader who imposes tariffs is imposing a tax on his own people. Just see the chain of events: Trump taxes the American people. In retaliation, Modi taxes the Indian people. Trump raises taxes. Modi raises taxes. Nationalists in both countries cheer. Interests groups in both countries laugh their way to the bank.

What kind of idiocy is this? How long will this lose-lose game continue?

The India Uncut Blog © 2010 Amit Varma. All rights reserved.
Follow me on Twitter.

ગુજરાત સ્થાપના દિવસ અંગે PM Modi એ Tweet કરીને ગુજરાતની જનતાને આપી શુભેચ્છાઓ

Modi સરકારે ત્રીજી વખત Lockdown માં કર્યો વધારો, જાણો કેટલા દિવસ સુધી રહેશે લોકડાઉન ?

ભારતમાં Coronavirus ની 30 રસી પર કામ શરૂ, PM Modi એ કરી સમીક્ષા

Buddha Purnima પર PM Modiએ કહ્યું, ભારત પોતાની વૈશ્વિક જવાબદારીનું કરી રહ્યું છે પાલન

વિશાખાપટ્ટનમ: ગેસ લિકેજ મામલે PM Modiનું ટ્વીટ, પરિસ્થિતિ પર રખાઈ રહી છે નજર

Cisco Content Security Virtual Appliance M380 IronPort remote cross site host modification demo exploit.

Russia remains fDi’s most diversified commodity economy, while second ranked Brazil has displaced Ukraine into third place. Cathy Mullan reports.

Construction resumed Oct. 4 on tunnel works after a brief work stoppage that began on Sept. 28 at the 20-MW Lower Modi Khola run-of-river hydropower facility.
 

Presentation by Russell Nowland of CommScope

The Americans and the French have been getting on well of late. President Francois Hollande’s successful visit to the White House in February is a case in point — despite the backdrop of his high-profile sex scandal.

The Alexander Devine Children's Cancer Trust v Millgate Developments Ltd and others [2018] EWCA Civ 2679 The Court of Appeal has refused to allow a property developer to modify a set of restrictive covenants, reversing the decision of the Upper Trib...

The Supreme Court has handed down its judgment in the long-awaited appeal of Rock Advertising Limited v MWB Business Exchange Centres Limited [2018] UKSC 24, a case which the court describes as “exceptional” on the basis it concerns two ...

Brazil's Real firmed for the first time this week, bouncing from last session's all-time lows, while most other Latin American currencies also strengthened on Friday on signs of easing tensions between the United States and China.

National Assembly Speaker Thandi Modise has expressed her disinterest in participating in any virtual meeting over the platform Zoom as the national legislature came under criticism on social media for opening itself to hacking.

...

Ninjala is sure to deliver Splatoon fans a new mess of fun and the rest of the world gets a peek at the buzz behind ...

NANKANA SAHIB: Punjab Governor Chudhary Muhammad Sarwar has said that the world has seen the RSS agenda of Modi government and its atrocities on innocent Kashmiris in the Indian Occupied Kashmir.He said this during his visit to the Gurdwara Janamasthan where he distributed ration bags among the...

NEW DELHI: Since the election results were announced last week — handing out a clear mandate to the Narendra Modi-led BJP — real estate brokers across the country have been prodding buyers to book their dream homes fast, since with a stable government on the cards, builders could increase prices any time soon. Business for thousands of brokers has been thin over the last year or so as negative sentiment engulfed the market and home sales tanked. Investors fled and genuine home buyers waited anxiously to see if a new stable government can infuse life into the economy. “It might just be a case of brokers trying to perk up […]

NEW DELHI: India’s top medical research body has turned down a proposal by the Modi government to test water from the Ganges river as a cure for coronavirus, ThePrint news portal said on Thursday.

It said the Indian Council of Medical Research (ICMR) turned down the government’s “request” to conduct research on a theory that Gangajal, or water from Ganges river, could possibly cure Covid-19.

Speaking to ThePrint, a source in the ICMR said the agency has refused to get involved as it is focussing on the Covid-19 battle and doesn’t want to waste time on other research amid the pandemic.

The move came after the country’s apex medical research body received a “request” from the Ministry of Jal Shakti to conduct “further research” on a proposal by an NGO, Atulya Ganga, said an ICMR official, who didn’t wish to be named.

In its letter last month, Mr Atulya had cited the presence of a “ninja virus”, called bacteriophage, in Ganges water that could cure Covid-19, the disease caused by the new coronavirus. Bacteriophage is a special type of virus that eats harmful bacteria, the letter said.

According ThePrint, the NGO asked the government on April 3 to conduct a study on the possibility of this virus acting as a cure. It sent a copy each to the ministry and the Prime Minister’s Office (PMO). The ministry’s National Mission for Clean Ganga, the department administering the Modi government’s ambitious Namami Gange programme, then wrote to ICMR on April 30 requesting a clinical trial.

The ICMR then held a meeting to discuss the idea, but refused to proceed, offering only its “help” to the NGO, ThePrint said. “We had indeed received a letter from the Ministry of Jal Shakti for such research. The experts at ICMR also held a meeting on this matter. Then we asked those proposing this research that you should tell us about hospitals and doctors that are ready and willing to conduct some research on it. We will certainly help them in this regard,” said the ICMR official.

“As of now we are still treating plasma therapy as a trial for treatment for corona (Covid-19), then how can we so quickly accept a virus called bacteriophage, found in the water of Ganges, as a cure? Right now, there is no logic in the argument that the virus found in Ganga’s water can indeed fight the coronavirus disease,” added the official.

However, he added that if the ministry takes an initiative into the matter then ICMR will extend its assistance to it.

Speaking to ThePrint, Dr Rajnikant Srivastava, ICMR’s head of the Department of Research Management, Policy Planning and Communication, in Delhi and Director of Regional Medical Research Centre, Gorakhpur, said: “A presentation was made after the Jal Shakti ministry’s proposal. The matter is at a very preliminary stage. Nothing has been decided on the future course of action. We will support the Jal Shakti ministry in all the work it does on this front.”

A senior official of the Ministry of Jal Shakti, meanwhile, said there are several special properties in the river and many people were demanding research on them.

Published in Dawn, May 8th, 2020

With the Narendra Modi government taking charge on Tuesday, real estate players hope the sector will get due priority, which will help bring the economy back to 8-9 percent growth. “The new government will pave way for realty reforms and take concrete steps to implement its promise given in the BJP manifesto to ensure housing for all in eight years,” Confederation of Real Estate Developers’ Associations of India (Credai) Lalit Kumar Jain said. The merger of Housing and Urban Development Department will ensure coordination and proper control, he said. “The new government will bring in a positive change to developers and buyers in the otherwise dark era that has been […]

Genetically modified diamondback moths designed to replace pesticides by wiping out female moths have been released in New York state

Modifying bacteria found in the guts of bees could help protect the insects against lethal infections affecting hives worldwide

Title: Fish Oil Doesn't Cut Failure Rate of Hemodialysis Grafts
Category: Health News
Created: 5/1/2012 6:05:00 PM
Last Editorial Review: 5/2/2012 12:00:00 AM

This article describes the development of medical competencies for oral medicine specialty training in the UK and Ireland by a collaborative working group using a modified Delphi technique. The current specialty training curriculum for oral medicine (OM) in the UK was developed by a working group including members of the British Society for Oral Medicine (BSOM) and members of the Specialty Advisory Committee for Additional Dental Specialties (SACADS) and adopted by the UK General Dental Council (GDC) in 2010. When the curriculum was developed, the entry requirements for specialty training in OM included undergraduate degrees in both dentistry and medicine. At the time of adoption, the requirement for a medical degree was removed. Medical competencies were assumed to have been delivered in medical undergraduate and postgraduate training. Accordingly, there was a need to define the medical competencies for OM specialty training to benefit trainees, trainers, and assessors. In 2018, a group comprising specialty trainers, recent former specialty trainees, and current specialty trainees in OM held face-to-face meetings in addition to email discussions and developed an updated curriculum document to better reflect the medical competencies required in specialty training. A collaborative modified Delphi approach was used to evaluate medical foundation competencies and to include only those that were considered relevant to OM specialty training. A list of relevant and achievable medical competencies was determined that has been approved by SACADS and will be incorporated into a revised OM curriculum from the UK GDC. The newly agreed-upon document for medical competencies in OM specialty training will serve as a reference for trainees, trainers, and assessors and reflects a successful use of a modified Delphi approach.

ABSTRACT

Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; however, the contributions of disease modifiers remain underappreciated. We exploited the Collaborative Cross (CC) mouse genetic-reference population to map genetic modifiers that affect the severity of Pseudomonas aeruginosa lung infection. Screening for P. aeruginosa respiratory infection in a cohort of 39 CC lines exhibits distinct disease phenotypes ranging from complete resistance to lethal disease. Based on major changes in the survival times, a quantitative-trait locus (QTL) was mapped on murine chromosome 3 to the genomic interval of Mb 110.4 to 120.5. Within this locus, composed of 31 protein-coding genes, two candidate genes, namely, dihydropyrimidine dehydrogenase (Dpyd) and sphingosine-1-phosphate receptor 1 (S1pr1), were identified according to the level of genome-wide significance and disease gene prioritization. Functional validation of the S1pr1 gene by pharmacological targeting in C57BL/6NCrl mice confirmed its relevance in P. aeruginosa pathophysiology. However, in a cohort of Canadian patients with cystic fibrosis (CF) disease, regional genetic-association analysis of the syntenic human locus on chromosome 1 (Mb 97.0 to 105.0) identified two single-nucleotide polymorphisms (rs10875080 and rs11582736) annotated to the Dpyd gene that were significantly associated with age at first P. aeruginosa infection. Thus, there is evidence that both genes might be implicated in this disease. Our results demonstrate that the discovery of murine modifier loci may generate information that is relevant to human disease progression.

IMPORTANCE Respiratory infection caused by P. aeruginosa is one of the most critical health burdens worldwide. People affected by P. aeruginosa infection include patients with a weakened immune system, such as those with cystic fibrosis (CF) genetic disease or non-CF bronchiectasis. Disease outcomes range from fatal pneumonia to chronic life-threatening infection and inflammation leading to the progressive deterioration of pulmonary function. The development of these respiratory infections is mediated by multiple causes. However, the genetic factors underlying infection susceptibility are poorly known and difficult to predict. Our study employed novel approaches and improved mouse disease models to identify genetic modifiers that affect the severity of P. aeruginosa lung infection. We identified candidate genes to enhance our understanding of P. aeruginosa infection in humans and provide a proof of concept that could be exploited for other human pathologies mediated by bacterial infection.

ABSTRACT

The malaria parasite Plasmodium falciparum traffics the virulence protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of infected red blood cells (RBCs) via membranous organelles, known as the Maurer’s clefts. We developed a method for efficient enrichment of Maurer’s clefts and profiled the protein composition of this trafficking organelle. We identified 13 previously uncharacterized or poorly characterized Maurer’s cleft proteins. We generated transfectants expressing green fluorescent protein (GFP) fusions of 7 proteins and confirmed their Maurer’s cleft location. Using co-immunoprecipitation and mass spectrometry, we generated an interaction map of proteins at the Maurer’s clefts. We identified two key clusters that may function in the loading and unloading of PfEMP1 into and out of the Maurer’s clefts. We focus on a putative PfEMP1 loading complex that includes the protein GEXP07/CX3CL1-binding protein 2 (CBP2). Disruption of GEXP07 causes Maurer’s cleft fragmentation, aberrant knobs, ablation of PfEMP1 surface expression, and loss of the PfEMP1-mediated adhesion. GEXP07 parasites have a growth advantage compared to wild-type parasites, and the infected RBCs are more deformable and more osmotically fragile.

IMPORTANCE The trafficking of the virulence antigen PfEMP1 and its presentation at the knob structures at the surface of parasite-infected RBCs are central to severe adhesion-related pathologies such as cerebral and placental malaria. This work adds to our understanding of how PfEMP1 is trafficked to the RBC membrane by defining the protein-protein interaction networks that function at the Maurer’s clefts controlling PfEMP1 loading and unloading. We characterize a protein needed for virulence protein trafficking and provide new insights into the mechanisms for host cell remodeling, parasite survival within the host, and virulence.

ABSTRACT

The capsule is the dominant Streptococcus pneumoniae virulence factor, yet how variation in capsule thickness is regulated is poorly understood. Here, we describe an unexpected relationship between mutation of adcAII, which encodes a zinc uptake lipoprotein, and capsule thickness. Partial deletion of adcAII in three of five capsular serotypes frequently resulted in a mucoid phenotype that biochemical analysis and electron microscopy of the D39 adcAII mutants confirmed was caused by markedly increased capsule thickness. Compared to D39, the hyperencapsulated adcAII mutant strain was more resistant to complement-mediated neutrophil killing and was hypervirulent in mouse models of invasive infection. Transcriptome analysis of D39 and the adcAII mutant identified major differences in transcription of the Sp_0505-0508 locus, which encodes an SpnD39III (ST5556II) type I restriction-modification system and allelic variation of which correlates with capsule thickness. A PCR assay demonstrated close linkage of the SpnD39IIIC and F alleles with the hyperencapsulated adcAII strains. However, transformation of adcAII with fixed SpnD39III alleles associated with normal capsule thickness did not revert the hyperencapsulated phenotype. Half of hyperencapsulated adcAII strains contained the same single nucleotide polymorphism in the capsule locus gene cps2E, which is required for the initiation of capsule synthesis. These results provide further evidence for the importance of the SpnD39III (ST5556II) type I restriction-modification system for modulating capsule thickness and identified an unexpected linkage between capsule thickness and mutation of adcAII. Further investigation will be needed to characterize how mutation of adcAII affects SpnD39III (ST5556II) allele dominance and results in the hyperencapsulated phenotype.

IMPORTANCE The Streptococcus pneumoniae capsule affects multiple interactions with the host including contributing to colonization and immune evasion. During infection, the capsule thickness varies, but the mechanisms regulating this are poorly understood. We have identified an unsuspected relationship between mutation of adcAII, a gene that encodes a zinc uptake lipoprotein, and capsule thickness. Mutation of adcAII resulted in a striking hyperencapsulated phenotype, increased resistance to complement-mediated neutrophil killing, and increased S. pneumoniae virulence in mouse models of infection. Transcriptome and PCR analysis linked the hyperencapsulated phenotype of the adcAII strain to specific alleles of the SpnD39III (ST5556II) type I restriction-modification system, a system which has previously been shown to affect capsule thickness. Our data provide further evidence for the importance of the SpnD39III (ST5556II) type I restriction-modification system for modulating capsule thickness and identify an unexpected link between capsule thickness and adcAII, further investigation of which could further characterize mechanisms of capsule regulation.

Photorespiration is an essential process in oxygenic photosynthetic organisms triggered by the oxygenase activity of Rubisco. In peroxisomes, photorespiratory HYDROXYPYRUVATE REDUCTASE1 (HPR1) catalyzes the conversion of hydroxypyruvate to glycerate together with the oxidation of a pyridine nucleotide cofactor. HPR1 regulation remains poorly understood; however, HPR1 phosphorylation at T335 has been reported. By comparing the kinetic properties of phosphomimetic (T335D), nonphosphorylatable (T335A), and wild-type recombinant Arabidopsis (Arabidopsis thaliana) HPR1, it was found that HPR1-T335D exhibits reduced NADH-dependent hydroxypyruvate reductase activity while showing improved NADPH-dependent activity. Complementation of the Arabidopsis hpr1-1 mutant by either wild-type HPR1 or HPR1-T335A fully complemented the photorespiratory growth phenotype of hpr1-1 in ambient air, whereas HPR1-T335D-containing hpr1-1 plants remained smaller and had lower photosynthetic CO₂ assimilation rates. Metabolite analyses indicated that these phenotypes were associated with subtle perturbations in the photorespiratory cycle of HPR1-T335D-complemented hpr1-1 rosettes compared to all other HPR1-containing lines. Therefore, T335 phosphorylation may play a role in the regulation of HPR1 activity in planta, although it was not required for growth under ambient air controlled conditions. Furthermore, improved NADP-dependent HPR1 activities in peroxisomes could not compensate for the reduced NADH-dependent HPR1 activity.

Endothelial activation and microvascular dysfunction are key pathogenic processes in severe malaria. We evaluated the early role of these processes in experimentally induced Plasmodium falciparum and P. vivax infection. Participants were enrolled in induced blood-stage malaria clinical trials. Plasma osteoprotegerin, angiopoietin-2, and von Willebrand Factor (vWF) levels were measured as biomarkers of endothelial activation. Microvascular function was assessed using peripheral arterial tonometry and near-infrared spectroscopy, and the endothelial glycocalyx was assessed by sublingual videomicroscopy and measurement of biomarkers of degradation. Forty-five healthy, malaria-naive participants were recruited from 5 studies. Osteoprotegerin and vWF levels increased in participants following inoculation with P. vivax (n = 16) or P. falciparum (n = 15), with the angiopoietin-2 level also increasing in participants following inoculation with P. falciparum. For both species, the most pronounced increase was seen in osteoprotegerin. This was particularly marked in participants inoculated with P. vivax, where the osteoprotegerin level correlated with the levels of parasitemia and the malaria clinical score. There were no changes in measures of endothelial glycocalyx or microvascular function. Plasma biomarkers of endothelial activation increased in early P. falciparum and P. vivax infection and preceded changes in the endothelial glycocalyx or microvascular function. The more pronounced increase in osteoprotegerin suggests that this biomarker may play a role in disease pathogenesis.

Although substantial progress has been made in depicting the molecular pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection, the comprehensive mechanism of HIV-1 latency and the most promising therapeutic strategies to effectively reactivate the HIV-1 latent reservoir to achieve a functional cure for AIDS remain to be systematically illuminated. Here, we demonstrated that piwi (P element-induced Wimpy)-like RNA-mediated gene silencing 4 (PIWIL4) played an important role in suppressing HIV-1 transcription and contributed to the latency state in HIV-1-infected cells through its recruitment of various suppressive factors, including heterochromatin protein 1α/β/, SETDB1, and HDAC4. The knockdown of PIWIL4 enhanced HIV-1 transcription and reversed HIV-1 latency in both HIV-1 latently infected Jurkat T cells and primary CD4⁺ T lymphocytes and resting CD4⁺ T lymphocytes from HIV-1-infected individuals on suppressive combined antiretroviral therapy (cART). Furthermore, in the absence of PIWIL4, HIV-1 latently infected Jurkat T cells were more sensitive to reactivation with vorinostat (suberoylanilide hydroxamic acid, or SAHA), JQ1, or prostratin. These findings indicated that PIWIL4 promotes HIV-1 latency by imposing repressive marks at the HIV-1 5' long terminal repeat. Thus, the manipulation of PIWIL4 could be a novel strategy for developing promising latency-reversing agents (LRAs).

IMPORTANCE HIV-1 latency is systematically modulated by host factors and viral proteins. During this process, the suppression of HIV-1 transcription plays an essential role in promoting HIV-1 latency. In this study, we found that PIWIL4 repressed HIV-1 promoter activity and maintained HIV-1 latency. In particular, we report that PIWIL4 can regulate gene expression through its association with the suppressive activity of HDAC4. Therefore, we have identified a new function for PIWIL4: it is not only a suppressor of endogenous retrotransposons but also plays an important role in inhibiting transcription and leading to latent infection of HIV-1, a well-known exogenous retrovirus. Our results also indicate a novel therapeutic target to reactivate the HIV-1 latent reservoir.

Purpose:

Clinical evidence shows minimal benefit to vitamin D screening and subsequent treatment in the general population. This study aims to assess the effectiveness of 2 light-touch interventions on reducing vitamin D test orders.

Methods:

The outcomes were weekly average vitamin D rates, computed from adult primary care encounters (preventive or nonpreventive) with a family medicine (FM) or internal medicine (IM) provider from June 14, 2018 through December 12, 2018. We conducted an interrupted time series analysis and estimated the cost impact of the interventions. The interventions consisted of an educational memo (August 9, 2018) distributed to providers and removal of the vitamin D test (FM: August 15, 2018; IM: October 17, 2018) from the providers’ quick order screen in the electronic health record. Change in order rates were analyzed among physicians (MDs and DOs), physician assistants (PAs), and nurse practitioners (NPs).

Results:

There were 587,506 primary care encounters (FM = 367,947; IM = 219,559). Vitamin D order rates decreased from 6.9% (FM = 5.1%; IM = 9.9%) to 5.2% (FM = 4% [P < .01], IM = 7.9% [P < .01]). For FM, the vitamin D test order rate continued to fall at a 0.08% per week rate after the interventions (end of study: 2.73%). The education intervention showed a relative decrease in each provider type (FM-physician = 16% [P < .01], FM-PA = 47% [P < .01], FM-NP = 20% [P = .01], IM-physician = 14% [P = .02], IM-PA = 52% [P < .01], IM-NP = 34% [P = .04]). Annualized savings was approximately 1 million dollars.

Conclusions:

Emailed evidence-based provider education may be an effective tool for modifying providers’ vitamin D test ordering behavior. The lack of the effectiveness of the vitamin D test removal from the quick order screen found for IM highlights the challenges facing simple electronic health record interventions when multiple alternate ordering pathways exist.

Background

Experimental and observational studies have raised concerns that giving intravenous (IV) iron to patients, such as individuals receiving maintenance hemodialysis, might increase the risk of infections. The Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial randomized 2141 patients undergoing maintenance hemodialysis for ESKD to a high-dose or a low-dose IV iron regimen, with a primary composite outcome of all-cause death, heart attack, stroke, or hospitalization for heart failure. Comparison of infection rates between the two groups was a prespecified secondary analysis.

Methods

Secondary end points included any infection, hospitalization for infection, and death from infection; we calculated cumulative event rates for these end points. We also interrogated the interaction between iron dose and vascular access (fistula versus catheter).

Results

We found no significant difference between the high-dose IV iron group compared with the lose-dose group in event rates for all infections (46.5% versus 45.5%, respectively, which represented incidences of 63.3 versus 69.4 per 100 patient years, respectively); rates of hospitalization for infection (29.6% versus 29.3%, respectively) also did not differ. We did find a significant association between risk of a first cardiovascular event and any infection in the previous 30 days. Compared with patients undergoing dialysis with an arteriovenous fistula, those doing so via a catheter had a higher incidence of having any infection, hospitalization for infection, or fatal infection, but IV iron dosing had no effect on these outcomes.

Conclusions

The high-dose and low-dose IV iron groups exhibited identical infection rates. Risk of a first cardiovascular event strongly associated with a recent infection.

Background

Fluid overload in patients undergoing hemodialysis contributes to cardiovascular morbidity and mortality. There is a global trend to lower dialysate sodium with the goal of reducing fluid overload.

Methods

To investigate whether lower dialysate sodium during hemodialysis reduces left ventricular mass, we conducted a randomized trial in which patients received either low-sodium dialysate (135 mM) or conventional dialysate (140 mM) for 12 months. We included participants who were aged >18 years old, had a predialysis serum sodium ≥135 mM, and were receiving hemodialysis at home or a self-care satellite facility. Exclusion criteria included hemodialysis frequency >3.5 times per week and use of sodium profiling or hemodiafiltration. The main outcome was left ventricular mass index by cardiac magnetic resonance imaging.

Results

The 99 participants had a median age of 51 years old; 67 were men, 31 had diabetes mellitus, and 59 had left ventricular hypertrophy. Over 12 months of follow-up, relative to control, a dialysate sodium concentration of 135 mmol/L did not change the left ventricular mass index, despite significant reductions at 6 and 12 months in interdialytic weight gain, in extracellular fluid volume, and in plasma B-type natriuretic peptide concentration (ratio of intervention to control). The intervention increased intradialytic hypotension (odds ratio [OR], 7.5; 95% confidence interval [95% CI], 1.1 to 49.8 at 6 months and OR, 3.6; 95% CI, 0.5 to 28.8 at 12 months). Five participants in the intervention arm could not complete the trial because of hypotension. We found no effect on health-related quality of life measures, perceived thirst or xerostomia, or dietary sodium intake.

Conclusions

Dialysate sodium of 135 mmol/L did not reduce left ventricular mass relative to control, despite improving fluid status.

Clinical Trial registry name and registration number:

The Australian New Zealand Clinical Trials Registry, ACTRN12611000975998.

BACKGROUND:Patients with cystic fibrosis develop decreased exercise capacity. However, the main factors responsible for this decline are still unclear. Thus, the objective of this study was to evaluate the factors influencing exercise capacity assessed with the modified shuttle test (MST) in individuals with cystic fibrosis.METHODS:A cross-sectional study was carried out in subjects with a diagnosis of cystic fibrosis who were 6–26 y old and were regularly monitored at 2 cystic fibrosis reference centers in Brazil. Individuals who were unable to perform the tests or who exhibited hemodynamic instability and exacerbation of respiratory symptoms were excluded. Anthropometric, clinical, and genotype data were collected. In addition, lung function and exercise capacity were evaluated with the MST.RESULTS:73 subjects (mean age 12.2 ± 4.9 y and FEV1 76.8 ± 23.3%) were included. The mean distance achieved in the MST was 765 ± 258 m (71.6% of predicted). The distance achieved on the MST correlated significantly with age (r = 0.49, P < .001), body mass index (r = 0.41, P < .001), resting heart rate (r = −0.51, P < .001), and FEV1 (r = 0.24, P = .042). Subjects with FEV1 > 67% of predicted (P = .02) and those with resting heart rate < 100 beats/min (P = .01) had a greater exercise capacity. Resting heart rate, age, and FEV1 (%) were found as significant variables to explain the distance achieved on the MST (R2 = 0.48, standard error = 191.0 m).CONCLUSIONS:The main determinants of exercise capacity assessed with the MST in individuals with cystic fibrosis were resting heart rate, age, and lung function.

Microscopy and rapid diagnostic tests (RDTs) are the main diagnostic tools for malaria but fail to detect low-density parasitemias that are important for maintaining malaria transmission. To complement existing diagnostic methods, an isothermal reverse transcription-recombinase polymerase amplification and lateral flow assay (RT-RPA) was developed. We compared the performance with that of ultrasensitive reverse transcription-quantitative PCR (uRT-qPCR) using nucleic acid extracts from blood samples (n = 114) obtained after standardized controlled human malaria infection (CHMI) with Plasmodium falciparum sporozoites. As a preliminary investigation, we also sampled asymptomatic individuals (n = 28) in an area of malaria endemicity (Lambaréné, Gabon) to validate RT-RPA and assess its performance with unprocessed blood samples (dbRT-RPA). In 114 samples analyzed from CHMI trials, the positive percent agreement to uRT-qPCR was 90% (95% confidence interval [CI], 80 to 96). The negative percent agreement was 100% (95% CI, 92 to 100). The lower limit of detection was 64 parasites/ml. In Gabon, RT-RPA was 100% accurate with asymptomatic volunteers (n = 28), while simplified dbRT-RPA showed 89% accuracy. In a subgroup analysis, RT-RPA detected 9/10 RT-qPCR-positive samples, while loop-mediated isothermal amplification (LAMP) detected 2/10. RT-RPA is a reliable diagnostic test for asymptomatic low-density infections. It is particularly useful in settings where uRT-qPCR is difficult to implement.

OBJECTIVE

We investigated the association between changes in weight status from childhood through adulthood and subsequent type 2 diabetes risks and whether educational attainment, smoking, and leisure time physical activity (LTPA) modify this association.

RESEARCH DESIGN AND METHODS

Using data from 10 Danish and Finnish cohorts including 25,283 individuals, childhood BMI at 7 and 12 years was categorized as normal or high using age- and sex-specific cutoffs (<85th or ≥85th percentile). Adult BMI (20–71 years) was categorized as nonobese or obese (<30.0 or ≥30.0 kg/m², respectively). Associations between BMI patterns and type 2 diabetes (989 women and 1,370 men) were analyzed using Cox proportional hazards regressions and meta-analysis techniques.

RESULTS

Compared with individuals with a normal BMI at 7 years and without adult obesity, those with a high BMI at 7 years and adult obesity had higher type 2 diabetes risks (hazard ratio [HR]_girls 5.04 [95% CI 3.92–6.48]; HR_boys 3.78 [95% CI 2.68–5.33]). Individuals with a high BMI at 7 years but without adult obesity did not have a higher risk (HR_girls 0.74 [95% CI 0.52–1.06]; HR_boys 0.93 [95% CI 0.65–1.33]). Education, smoking, and LTPA were associated with diabetes risks but did not modify or confound the associations with BMI changes. Results for 12 years of age were similar.

CONCLUSIONS

A high BMI in childhood was associated with higher type 2 diabetes risks only if individuals also had obesity in adulthood. These associations were not influenced by educational and lifestyle factors, indicating that BMI is similarly related to the risk across all levels of these factors.

Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain.We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk.We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR.We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age.